bluuebunny/crossref_metadata_2025 huggingface dataset:
Article 101 TFEU: The Elements
Authors: Alison Jones , Brenda Sufrin , Niamh Dunne
Published: June 2024

This chapter discusses the text and scheme of Article 101 which prohibits agreements, decisions, and concerted practices which restrict competition and affect trade between Member States. It explains the terms employed in Article 101(1) and how they are interpreted and applied. In particular, it discusses: the meaning of ‘undertaking’ and ‘association of undertakings’, including the concepts of ‘economic activities’ and of a ‘single economic entity’; the meaning of ‘agreement’ including the coverage of both horizontal and vertical agreements; the meaning of ‘concerted practice’; the meaning of ‘decisions by associations of undertakings’; the application of Article 101(1) to complex arrangements and single continuous infringements; and the meaning of an appreciable effect on trade between Member States.
Article 102 TFEU: Conduct Which Can be an Abuse
Authors: Alison Jones , Brenda Sufrin , Niamh Dunne
Published: June 2024

This chapter discusses the difficult concept of what constitutes an ‘abuse’ of a dominant position for the purposes of Article 102. It considers the case law of the EU Courts, the decisional practice of the Commission, and the Commission’s Guidance Paper on enforcement priorities, and the problem of distinguishing competition on the merits from illegitimate conduct. The chapter looks at the different classifications of abuse, particularly exclusionary and exploitative abuses; the distinction between form- and effects-based approaches to types of abuse; the leveraging of market power between distinct markets as a theory of harm; the objective justification defence; and general issues in respect of abuses concerning prices, including the ‘as efficient competitor’ test. The chapter then examines the application of Article 102 to various forms of conduct, including: price discrimination; predatory pricing; selective low pricing; margin squeeze; exclusive dealing; tying and bundling; refusal to supply; self-preferencing; malicious pursuit of legal proceedings; ‘regulatory gaming’; discrimination abuses; unfairly high and low pricing; and hindering inter-Member State trade.
Competition and the State: Article 106 TFEU
Authors: Alison Jones , Brenda Sufrin , Niamh Dunne
Published: June 2024

This chapter examines how competition law applies to the actions of the State when it intervenes in the market through undertakings which it controls or owns or which it places in a privileged position. The discussion includes the principle of Union loyalty in Article 4(3) TEU; Article 106(1); Article 106(2); and the Commission’s supervisory and policing powers in Article 106(3). Article 106(1) is a prohibition addressed to Member States against enacting or maintaining in force any measure in relation to public undertakings or undertakings to which they have granted special or exclusive rights which are contrary to the Treaty rules. The chapter discusses what is meant by ‘public undertakings’ and ‘special or exclusive rights’ and examines in the light of the case law what measures are forbidden by Article 106(1), including those involving the cumulation of rights, the extension of a dominant position from one market to another, and the creation of situations of inequality of opportunity. Article 106(2) gives a limited derogation from Article 106(2) to undertakings entrusted with the operation of services of general economic interest (SGEIs). The chapter discusses the concept of ‘services of general economic interest’ and examines the cases in which the derogation has been applied or not applied, including the application of Article 106(2) to compensation for the provision of SGEIs which constitutes State aid. The chapter also considers Article 106(3) and the question of the direct effect of Article 106(1) and (2).
Mergers
Authors: Alison Jones , Brenda Sufrin , Niamh Dunne
Published: June 2024

This chapter discusses the regime for controlling mergers which have an ‘EU dimension’ under the European Union Merger Regulation (EUMR). The chapter examines: the purposes of merger control; the history of the EUMR; the scheme of the EUMR and the concept of the ‘one-stop shop’; jurisdiction under the EUMR, including the definition of a ‘concentration’ and what amounts to an ‘EU dimension’; procedure, including Phase I and Phase II proceedings; the substantive appraisal of horizontal, and non-horizontal, mergers under the EUMR and the test of significantly impeding effective competition (SIEC); EUMR statistics; appeals; and international issues. It considers current controversial issues, including whether merger control is sufficiently rigorous, how acquisitions of start-ups or impacting on innovation should be assessed, whether a new substantive test for appraisal of mergers is required, and whether, and if so when, public interest (or non-competition) factors, such as the impact of a concentration on jobs, equality, sustainability, democracy, industrial policy, or national security, should affect the appraisal of a merger.
International Aspects
Authors: Alison Jones , Brenda Sufrin , Niamh Dunne
Published: June 2024

This chapter examines the issue of jurisdictional problems in competition law, the ‘internationalisation’ of competition law, and the efforts to deal with competition issues at a global level to match the global operations of undertakings on world markets. It looks first at the question of extraterritoriality in public international law, particularly the concept of objective territoriality. It considers the distinction between prescriptive jurisdiction and enforcement jurisdiction and how these might apply to competition law. It then looks at the development of the effects doctrine in US law and the concept of comity, and at the position of foreign plaintiffs in US courts. It considers how the EU takes jurisdiction by the application of the single economic entity doctrine, the implementation doctrine, and the qualified effects doctrine. The chapter concludes by examining international cooperation in competition law and how competition law must be sensitive to the huge global economic inequalities of the twenty-first century. It looks at the bilateral agreements into which the EU has entered, and the multilateral cooperation to which the EU is party, including cooperation within UNCTAD, the OECD, the WTO, and the International Competition Network (ICN).
Observations and detectability of young Suns’ flaring and CME activity in optical spectra
Authors: Leitzinger M , Odert P , Greimel R
Published: June 2024

The Sun’s history is still a subject of interest to modern astrophysics. Observationally constrained rates of Coronal Mass Ejections (CMEs) of young solar analogues are still lacking, as those require dedicated monitoring. We present medium-resolution optical spectroscopic monitoring of a small sample of bright and prominent solar analogues over a period of 3 yr using the 0.5-m telescope at observatory Lustbühel Graz (OLG) of the University of Graz, Austria. The aim is the detection of flares and CMEs from those spectra. In more than 1700 h of spectroscopic monitoring, we found signatures of four flares and one filament eruption on EK Dra which has been reported in previous literature, but we complementarily extended the data to cover the latter phase. The other stars did not reveal detectable signatures of activity. For these non-detections, we derive upper limits of occurrence rates of very massive CMEs, which are detectable with our observational setup, ranging from 0.1 to 2.2 d−1, but these may be even smaller than the given rates considering observational biases. Furthermore, we investigate the detectability of flares/CMEs in OLG spectra by utilizing solar 2D Hα spectra from Mees Solar Observatory. We find that solar-sized events are not detectable within our observations. By scaling up the size of the solar event, we show that with a fractional active region area of 18 per cent in residual spectra and 24 per cent in equivalent width time series derived from the same residuals that solar events are detectable if they had hypothetically occurred on HN Peg.
Structural characterization of two prototypical repressors of SorC family reveals tetrameric assemblies on DNA and mechanism of function
Authors: Šoltysová Markéta , Škerlová Jana , Pachl Petr , Škubník Karel , Fábry Milan , Sieglová Irena , Farolfi Martina , Grishkovskaya Irina , Babiak Michal , Nováček Jiří , Krásný Libor , Řezáčová Pavlína
Published: June 2024

The SorC family of transcriptional regulators plays a crucial role in controlling the carbohydrate metabolism and quorum sensing. We employed an integrative approach combining X-ray crystallography and cryo-electron microscopy to investigate architecture and functional mechanism of two prototypical representatives of two sub-classes of the SorC family: DeoR and CggR from Bacillus subtilis. Despite possessing distinct DNA-binding domains, both proteins form similar tetrameric assemblies when bound to their respective DNA operators. Structural analysis elucidates the process by which the CggR-regulated gapA operon is derepressed through the action of two effectors: fructose-1,6-bisphosphate and newly confirmed dihydroxyacetone phosphate. Our findings provide the first comprehensive understanding of the DNA binding mechanism of the SorC-family proteins, shedding new light on their functional characteristics.
AlphaKnot 2.0: a web server for the visualization of proteins’ knotting and a database of knotted AlphaFold-predicted models
Authors: Rubach Pawel , Sikora Maciej , Jarmolinska Aleksandra I , Perlinska Agata P , Sulkowska Joanna I
Published: June 2024

The availability of 3D protein models is rapidly increasing with the development of structure prediction algorithms. With the expanding availability of data, new ways of analysis, especially topological analysis, of those predictions are becoming necessary. Here, we present the updated version of the AlphaKnot service that provides a straightforward way of analyzing structure topology. It was designed specifically to determine knot types of the predicted structure models, however, it can be used for all structures, including the ones solved experimentally. AlphaKnot 2.0 provides the user’s ability to obtain the knowledge necessary to assess the topological correctness of the model. Both probabilistic and deterministic knot detection methods are available, together with various visualizations (including a trajectory of simplification steps to highlight the topological complexities). Moreover, the web server provides a list of proteins similar to the queried model within AlphaKnot’s database and returns their knot types for direct comparison. We pre-calculated the topology of high-quality models from the AlphaFold Database (4th version) and there are now more than 680.000 knotted models available in the AlphaKnot database. AlphaKnot 2.0 is available at https://alphaknot.cent.uw.edu.pl/.
Insights into the molecular mechanism of ParABS system in chromosome partition by HpParA and HpParB
Authors: Chu Chen-Hsi , Wu Che-Ting , Lin Min-Guan , Yen Cheng-Yi , Wu Yi-Zhan , Hsiao Chwan-Deng , Sun Yuh-Ju
Published: June 2024

The ParABS system, composed of ParA (an ATPase), ParB (a DNA binding protein), and parS (a centromere-like DNA), regulates bacterial chromosome partition. The ParB-parS partition complex interacts with the nucleoid-bound ParA to form the nucleoid-adaptor complex (NAC). In Helicobacter pylori, ParA and ParB homologs are encoded as HpSoj and HpSpo0J (HpParA and HpParB), respectively. We determined the crystal structures of the ATP hydrolysis deficient mutant, HpParAD41A, and the HpParAD41A-DNA complex. We assayed the CTPase activity of HpParB and identified two potential DNA binding modes of HpParB regulated by CTP, one is the specific DNA binding by the DNA binding domain and the other is the non-specific DNA binding through the C-terminal domain under the regulation of CTP. We observed an interaction between HpParAD41A and the N-terminus fragment of HpParB (residue 1–10, HpParBN10) and determined the crystal structure of the ternary complex, HpParAD41A-DNA-HpParBN10 complex which mimics the NAC formation. HpParBN10 binds near the HpParAD41A dimer interface and is clamped by flexible loops, L23 and L34, through a specific cation-π interaction between Arg9 of HpParBN10 and Phe52 of HpParAD41A. We propose a molecular mechanism model of the ParABS system providing insight into chromosome partition in bacteria.
Cooperation of regulatory RNA and the RNA degradosome in transcript surveillance
Authors: Bandyra Katarzyna J , Fröhlich Kathrin S , Vogel Jörg , Rodnina Marina , Goyal Akanksha , Luisi Ben F
Published: June 2024

The ompD transcript, encoding an outer membrane porin in Salmonella, harbors a controlling element in its coding region that base-pairs imperfectly with a ‘seed’ region of the small regulatory RNA (sRNA) MicC. When tagged with the sRNA, the ompD mRNA is cleaved downstream of the pairing site by the conserved endoribonuclease RNase E, leading to transcript destruction. We observe that the sRNA-induced cleavage site is accessible to RNase E in vitro upon recruitment of ompD into the 30S translation pre-initiation complex (PIC) in the presence of the degradosome components. Evaluation of substrate accessibility suggests that the paused 30S PIC presents the mRNA for targeted recognition and degradation. Ribonuclease activity on PIC-bound ompD is critically dependent on the recruitment of RNase E into the multi-enzyme RNA degradosome, and our data suggest a process of substrate capture and handover to catalytic sites within the degradosome, in which sequential steps of seed matching and duplex remodelling contribute to cleavage efficiency. Our findings support a putative mechanism of surveillance at translation that potentially terminates gene expression efficiently and rapidly in response to signals provided by regulatory RNA.
The Role of e-Cigarette Packaging as a Health Communications Tool: A Focus Group Study With Adolescents and Adults in England and Scotland
Authors: Jones Daniel , Morgan Amber , Moodie Crawford , Alexandrou Georgia , Ford Allison , Mitchell Danielle
Published: June 2024

Introduction

In the United Kingdom, e-cigarette and refill packaging must display a nicotine addiction warning. This study explored how this message is perceived, responses to alternative on-pack messages, and other options for using e-cigarette packaging to discourage youth and people who neither smoke nor use e-cigarettes while encouraging smokers to switch.

Aims and Methods

Between August and September 2022, 16 focus groups (n = 70) were conducted to explore these topics with adolescents (n = 31, aged 11–17 years) and adults (n = 39, nonsmokers, smokers that use e-cigarettes, smokers that do not use e-cigarettes) in England and Scotland.

Results

While several participants thought the current nicotine addiction warning could help increase awareness of nicotine addiction, most reported that it failed to capture attention and was not a deterrent. Alternative messages shown on packs (about harm, toxicity, wellness, litter, or relative risk) received mixed responses. Relative risk messages were perceived as most beneficial for smokers switching but also thought to potentially encourage uptake among nonsmokers. Some participants considered certain harm and toxicity messages to potentially dissuade uptake. Participants proposed several ideas to reduce the appeal of e-cigarette packaging and devices to deter youth uptake, including more prominent warnings, standardized packaging, and devices that are plain or include health messages.

Conclusions

Packaging can play a crucial role in communicating product and health messages to different consumer groups. Further consideration of how packaging and labeling can meet the needs of non-nicotine users while simultaneously reaching those who may benefit from using e-cigarettes to stop smoking is warranted.

Implications

While some viewed the nicotine addiction warning required on e-cigarettes and refill packaging in the United Kingdom as helpful in raising awareness of nicotine addiction, it did not resonate with most of our sample of adolescents and adults. The findings suggest that e-cigarette packaging could be better used to encourage smokers to switch to a less harmful alternative, with relative risk messages showing promise. Furthermore, strengthening on-pack messaging (eg increasing salience and rotating messages) and reducing the appeal of packaging (eg drab colors) and devices (eg including warnings) may help increase awareness of e-cigarette harms while deterring use among adolescents and nonsmokers.
Managing Fear Responses: A Qualitative Analysis of Pictorial Warning Labels Five Years Post-Plain Packaging
Authors: Ozarka Ellen , Teddy Lani , Blank Mei-Ling , Waa Andrew , Hoek Janet
Published: June 2024

Introduction

Although pictorial warning labels (PWLs) now dominate tobacco packages sold in many countries, few studies have probed how people who smoke respond to the threats presented several years post-plain packaging and larger PWLs. Understanding how people manage the fear and dissonance PWLs arouse, and the strategies they use to rationalize, diminish, and reject risk messages, could inform future PWL design.

Aims and Methods

We undertook 27 in-depth interviews with people aged 18 and over (16 female, 8 Māori, and 13 aged ≤35) who smoked roll-your-own tobacco and lived in Aotearoa New Zealand. We probed participants’ views on current PWLs and how they responded to these, then asked them to use alternative images and headlines to create new PWLs. We drew on the extended parallel processing model to interpret the data, which we analyzed using a reflexive thematic analysis approach.

Results

People who smoke dislike PWLs, which they think reduce them to diseased body parts. While a minority thought existing PWLs were believable and effective, most reported avoiding PWLs by hiding or cognitively blocking them. Participants used diverse counterarguments to diminish PWLs’ relevance and impact, and a minority displayed strong reactance. Several suggested developing PWLs that recognized them as whole people rather than patients in waiting, and recommended greater use of testimonials, particularly from people who had successfully become smoke free.

Conclusions

PWLs using more holistic and diverse messages could elicit greater engagement and responsiveness, and motivate cessation more effectively than existing health-oriented warnings.

Implications

Our findings suggest existing PWLs, which aim to arouse fear of ill health, could be complemented by warnings that emphasize the benefits of quitting. Continuing to use threat-based PWLs could stimulate greater rationalization and reactance. By contrast, PWLs that aim to illustrate how cessation could benefit people who smoke and their families, rather than instill a fear of disease, could avoid message rejection and counter-argument, and may prove a more powerful way of motivating cessation.
Genetic variability of aquaporin expression in maize: From eQTLs to a MITE insertion regulating PIP2;5 expression
Authors: Maistriaux Laurie C , Laurent Maxime J , Jeanguenin Linda , Prado Santiago Alvarez , Nader Joseph , Welcker Claude , Charcosset Alain , Tardieu François , Nicolas Stéphane D , Chaumont François
Published: June 2024

Plant aquaporins are involved in numerous physiological processes, such as cellular homeostasis, tissue hydraulics, transpiration, and nutrient supply, and are key players of the response to environmental cues. While varying expression patterns of aquaporin genes have been described across organs, developmental stages, and stress conditions, the underlying regulation mechanisms remain elusive. Hence, this work aimed to shed light on the expression variability of 4 plasma membrane intrinsic protein (PIP) genes in maize (Zea mays) leaves, and its genetic causes, through expression quantitative trait locus (eQTL) mapping across a 252-hybrid diversity panel. Significant genetic variability in PIP transcript abundance was observed to different extents depending on the isoforms. The genome-wide association study mapped numerous eQTLs, both local and distant, thus emphasizing the existing natural diversity of PIP gene expression across the studied panel and the potential to reveal regulatory actors and mechanisms. One eQTL associated with PIP2;5 expression variation was characterized. Genomic sequence comparison and in vivo reporter assay attributed, at least partly, the local eQTL to a transposon-containing polymorphism in the PIP2;5 promoter. This work paves the way to the molecular understanding of PIP gene regulation and its possible integration into larger networks regulating physiological and stress adaptation processes.
Discovery of small molecule guanylyl cyclase B receptor positive allosteric modulators
Authors: Ma Xiao , Peddibhotla Satyamaheshwar , Zheng Ye , Pan Shuchong , Mehta Alka , Moroni Dante G , Chen Qi-Yin , Ma Xiaoyu , Burnett John C , Malany Siobhan , Sangaralingham S Jeson
Published: June 2024

Myocardial fibrosis is a pathological hallmark of cardiovascular disease (CVD), and excessive fibrosis can lead to new-onset heart failure and increased mortality. Currently, pharmacological therapies for myocardial fibrosis are limited, highlighting the need for novel therapeutic approaches. The particulate guanylyl cyclase B (GC-B) receptor possesses beneficial antifibrotic actions through the binding of its natural ligand C-type natriuretic peptide (CNP) and the generation of the intracellular second messenger, cyclic guanosine 3′,5′-monophosphate (cGMP). These actions include the suppression of fibroblast proliferation and reduction in collagen synthesis. With its abundant expression on fibroblasts, the GC-B receptor has emerged as a key molecular target for innovative CVD therapeutics. However, small molecules that can bind and potentiate the GC-B/cGMP pathway have yet to be discovered. From a cell-based high-throughput screening initiative of the NIH Molecular Libraries Small Molecule Repository and hit-to-lead evolution based on a series of structure–activity relationships, we report the successful discovery of MCUF-42, a GC-B-targeted small molecule that acts as a positive allosteric modulator (PAM). Studies herein support MCUF-42's ability to enhance the binding affinity between GC-B and CNP. Moreover, MCUF-42 potentiated cGMP levels induced by CNP in human cardiac fibroblasts (HCFs) and notably also enhanced the inhibitory effect of CNP on HCF proliferation. Together, our findings highlight that MCUF-42 is a small molecule that can modulate the GC-B/cGMP signaling pathway, potentially enhancing the antifibrotic actions of CNP. Thus, these data underscore the continued development of GC-B small molecule PAMs as a novel therapeutic strategy for targeting cardiac fibrosis and CVD.
Double Citizenship as a Double-Edged Sword: Young Return Migrants’ Code-Switching for Belonging in Mexico
Authors: Ramírez Adriana P
Published: June 2024

In the past two decades, a growing number of Mexican migrants have left the United States to return to Mexico. Few studies have focused on the (re)integration process of these return migrants, especially children and young adults. Using semi-structured interviews, my study addresses this gap by asking how young return migrants adapt in Mexico and negotiate belonging in their communities. I argue that Mexican-U.S. dual citizenship is significant in Mexico in both a legal and cultural sense and operates as a type of double-edged sword—one that, on the one hand, provides youth with opportunities for advancement, but on the other, impedes cultural belonging. Young return migrants navigate this contradiction by learning to code-switch across different life stages and thus, selectively hiding and highlighting their U.S. ties to gain belonging and better economic opportunities. This article illuminates the ways that citizenship is an acquired and learned process that significantly marks the lives of return migrants.
Patient selection for nonoperating room anesthesia
Authors: Georgiadis Paige L. , Tsai Mitchell H. , Routman Justin S.
Published: June 2024

Purpose of review

Given the rapid growth of nonoperating room anesthesia (NORA) in recent years, it is essential to review its unique challenges as well as strategies for patient selection and care optimization.

Recent findings

Recent investigations have uncovered an increasing prevalence of older and higher ASA physical status patients in NORA settings. Although closed claim data regarding patient injury demonstrate a lower proportion of NORA cases resulting in a claim than traditional operating room cases, NORA cases have an increased risk of claim for death. Challenges within NORA include site-specific differences, limitations in ergonomic design, and increased stress among anesthesia providers. Several authors have thus proposed strategies focusing on standardizing processes, site-specific protocols, and ergonomic improvements to mitigate risks.

Considering the unique challenges of NORA settings, meticulous patient selection, risk stratification, and preoperative optimization are crucial. Embracing data-driven strategies and leveraging technological innovations (such as artificial intelligence) is imperative to refine quality control methods in targeted areas. Collaborative efforts led by anesthesia providers will ensure personalized, well tolerated, and improved patient outcomes across all phases of NORA care.
Opioid-free general anesthesia: considerations, techniques, and limitations
Authors: Shanthanna Harsha , Joshi Girish P.
Published: June 2024

Purpose of review

To discuss the role of opioids during general anesthesia and examine their advantages and risks in the context of clinical practice. We define opioid-free anesthesia (OFA) as the absolute avoidance of intraoperative opioids.

Recent findings

In most minimally invasive and short-duration procedures, nonopioid analgesics, analgesic adjuvants, and local/regional analgesia can significantly spare the amount of intraoperative opioid needed. OFA should be considered in the context of tailoring to a specific patient and procedure, not as a universal approach. Strategies considered for OFA involve several adjuncts with low therapeutic range, requiring continuous infusions and resources, with potential for delayed recovery or other side effects, including increased short-term and long-term pain. No evidence indicates that OFA leads to decreased long-term opioid-related harms.

Complete avoidance of intraoperative opioids remains questionable, as it does not necessarily ensure avoidance of postoperative opioids. Multimodal analgesia including local/regional anesthesia may allow OFA for selected, minimally invasive surgeries, but further research is necessary in surgeries with high postoperative opioid requirements. Until there is definitive evidence regarding procedure and patient-specific combinations as well as the dose and duration of administration of adjunct agents, it is imperative to practice opioid-sparing approach in the intraoperative period.
Strategies for Minimizing the Effects of Observer Variability on Sagittal Parameter Measurements of the Spine
Authors: dos Santos Delgado Adimilson , Souza Morais Bruna , Luiz Aparecido Defino Helton , Neto Montagnoli Arlindo
Published: June 2024

Study Design:

Exploratory-descriptive study.

Objective:

Evaluate the influence of observer variability on the measurements of both thoracic kyphosis (TK) and lumbar lordosis (LL) obtained with anatomic and functional spinal segmentation methods.

Background:

Parametric analysis for spinal surgery planning typically relies on anatomic parameters. However, incorporating functional parameters that consider the vertebrae orientation is important to minimizing surgical calculation errors.

Methods:

The authors developed parametric analysis software that integrates traditional and functional methodologies. The proposed method included functional thoracic kyphosis and functional lumbar lordosis calculated from the lines normal to the inflection points of the spine model. Using a synthetic lateral X-ray, the observer variability was computer-simulated generating 20 landmark sets that replicate the annotations of 20 observers. The analysis also included 10 clinical X-rays, annotated twice by 3 judges with a minimum 1-week interval. The spinal curvature angles were derived using the anatomic and functional methods. Statistical analysis were performed for comparison.

Results:

For the synthetic X-ray, the proposed method presented significantly less variability: TK (<±2.5 degrees, P=0.00023) and LL (<±5 degrees, P=0.00012). For the clinical X-rays, the interobserver reliability analysis yielded higher intraclass correlation coefficients (ICC) for functional TK (ICC>0.97) and functional LL (ICC>0.87) than for TK (ICC<0.91) and LL (ICC<0.89). Statistically significant differences were observed for both TK (P=0.001) and LL (P=0.030). Under the traditional method, observer variability led to measurement differences surpassing ±19 degrees, whereas differences with the proposed method were within ±10 degrees for both parameters.

Conclusion:

The vertebral endplate is not the most suitable place to measure spinal sagittal curvatures. Small changes in landmark position significantly alter the measured Cobb angle. The proposed method offers a substantial advantage regarding the influence of observer variability, in addition to the more individualized analysis.
To establish a prognostic model of epidermal growth factor receptor mutated non-small cell lung cancer patients based on Least Absolute Shrinkage and Selection Operator regression
Authors: Li Bowen , Zhang Xiaopeng
Published: June 2024

Background

There is currently a shortage of effective diagnostic tools that are used for identifying long-term survival among non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations. This research utilized the development of a prognostic model to assist clinicians in forecasting the survival over 24 months.

Methods

In Phase III and IV those patients who were diagnosed with EGFR mutation from January 2018 to June 2022 were enrolled into the lung cancer group of Thoracic Surgery Department of Hebei Provincial People’s Hospital. Long-run survival was stated as survival for 24 months after being diagnosed. A multivariate prognostic pattern was constructed by means of internal validation and binary logistic regression by bootstrapping. One nomogram was created with a view to boosting the explanation and applicability of the pattern.

Results

A total of 603 patients with EGFR mutation were registered. Elements linked to the whole survival beyond 24 months were age (OR 6.15); female (OR 1.79); functional status (ECOG 0–1) (OR 5.26); Exon 20 insertion mutation deletion (OR 2.08); No central nervous system metastasis (OR 2.66), targeted therapy (OR 0.43); Immunotherapy (OR 0.24). The model has good internal validation.

Conclusion

Seven pretreatment clinicopathological variables predicted survival over 24 months. That pattern owns a great discriminative capability. It is hypothesized that this pattern is capable of assisting in selecting the optimal treatment sequence for NSCLC patients with EGFR mutations.
Melanocytic Nevus With Spindle Cell Lipomatous Metaplasia
Authors: Urso Carmelo
Published: June 2024

Melanocytic nevi can show a great number of morphological, cytoarchitectural, and stromal variations. Some of these histopathological patterns, infrequent or unusual, can occasionally produce diagnostic doubts or problems. A 22-year-old female patient presented a poorly pigmented cutaneous polypoid lesion of the scalp. Histopathological examination showed an intradermal melanocytic nevus composed of aggregates, nests, and cords of benign melanocytes, with collagenous stroma and large lipomatous areas. In the lipidized portion of the lesion, nevus cells, arranged in clusters, nests, and cords, were intimately associated with mature-appearing adipocytes, CD34-positive spindle cells, Alcian Blue–positive fibromyxoid stroma, and eosinophilic collagen bundles, findings resembling those typically seen in spindle cell lipoma. Spindle cell lipomatous metaplasia, rarely observed in some benign nonmelanocytic skin lesions, can be considered an additional unusual, not previously described, stromal variation occurring in melanocytic nevi.
Immunoexpression Patterns of Adhesion Molecules (E-cadherin, β-catenin, CD56) and Cytokeratins (CK19, CK20, HMWCK, CAM5.2) During Hair Development in Human Fetuses Compared With Adults
Authors: Zorlu Özge , Karabağ Sevil , Erdoğan Kıvılcım E. , Aksın Merve , Üstün Batuhan
Published: June 2024

Abnormalities in the expression of cytokeratins or adhesion molecules have been associated with hair disorders. The expression patterns of these molecules in the hair follicles of developing human fetuses are not obvious. We aimed to investigate the expression patterns of some cytokeratins and adhesion molecules in the hair follicle of human fetuses and compared them with adults. Forty-eight fetuses of >16 gestational weeks and 22 adult cases with total excisions of benign nevi or cysts were enrolled. The skin samples were taken from both the scalp and back of the fetuses. The histopathologically normal skin areas were evaluated in adults. CK19, CK20, CAM5.2, high-molecular-weight cytokeratin, E-cadherin, β-catenin, and CD56 immunohistochemical stainings were performed. In the fetus group, the staining scores declined in the third trimester but elevated and reached the highest level in adults, except for CD56, which did not stain any adult samples. All stainings were mostly observed in the outer root sheath, except CD56 that stained the perifollicular dermal sheath only in fetuses. E-cadherin, β-catenin, and high-molecular-weight cytokeratin strongly and diffusely stained all adult samples. CAM5.2 and CK19 scores were correlated in fetuses (scalp scores: rs = 0.405, P = 0.004; back scores: rs = 0.422, P = 0.003) and adults (back scores: rs = 0.562, P = 0.046). CD56 negativity indicated the immune-privilege feature of adult hair follicles. As CK19, CAM5.2 may be used to find the regions of stem cells or transient amplifying cells.
Cutaneous Seeding of Glioblastoma: A Case Report and Literature Review
Authors: Knittel Ronan , Rogers Sasha , Wood Benjamin A.
Published: June 2024

We present the case of a 61-year-old male patient with a history of intracranial IDH-wildtype glioblastoma with an isolated cutaneous metastasis within the previous surgical site scar. The cytomorphology of the cutaneous deposits was reminiscent of metastatic melanoma, which is a differential diagnostic pitfall. The tumor molecular characteristics are described, as these have become essential diagnostic criteria for many central nervous system tumors, along with a discussion of the role of immunohistochemical markers and potential pitfalls in the differential diagnosis of melanoma and poorly differentiated carcinoma. We discuss the biology of metastatic glioblastoma and provide a focused literature review of previous glioblastomas with tumor cell seeding within prior surgical scars.
Acute Interstitial Inflammation on Skin Biopsies and Positive Tissue Cultures in Cellulitis Patients Are Associated a Worse Prognosis
Authors: Libson Karissa , Barba Johnny , Henning Ania , Fisher Kristopher , Kirven Rachel M. , Korman Abraham M. , Plaza Jose A. , Kaffenberger Benjamin H. , Chung Catherine
Published: June 2024

Background:

Cellulitis is a significant public health burden and lacks a gold standard for diagnosis. Up to 1/3 of patients are incorrectly diagnosed. The skin biopsy has been proposed as the gold standard.

Objective:

In this study, we evaluate the histopathologic characteristics and tissue culture positivity of biopsies in patients diagnosed with cellulitis seen by our inpatient dermatology consultation service.

Methods:

This retrospective cohort study examined patients who were hospitalized with a skin and soft tissue infection at our institution between 2011 and 2020 and underwent a skin biopsy.

Results:

Those with a positive tissue culture were more likely to die within 30 days compared with those with negative tissue cultures (26% vs. 6%, P = 0.048). Patients who died within 30 days were more likely to have acute interstitial inflammation as a feature on histopathology (38%, P = 0.03).

Limitations:

Single institutional design, unintentional exclusion of patients with organism-specific diagnosis, and selection for a medically complex patient population because of the nonroutine collection of biopsies.

Conclusion:

Positive tissue cultures and histopathology showing acute interstitial space inflammation on skin and soft tissue infection (SSTI) biopsies are associated with increased mortality and thus may serve as indicators of poor prognosis.
Nutrition during noninvasive respiratory support
Authors: Singer Pierre , Robinson Eyal , Hellerman-Itzhaki Moran
Published: June 2024

Purpose of review

The use of noninvasive techniques [noninvasive ventilation (NIV) or high flow nasal cannula (HFNC) oxygen therapy] to support oxygenation and/or ventilation in patients with respiratory failure has become widespread, even more so since the coronavirus disease 2019 pandemic. The use of these modalities may impair the patient's ability to eat. “To breath or to eat” may become a dilemma. In this review, we identify the patients at risk of malnutrition that require medical nutritional therapy and understand the mechanisms of function of the devices to better give adapted nutritional indications for noninvasive ventilation or high flow nasal cannula.

Recent findings

The Global Leadership Initiative for Malnutrition has been validated in the Intensive Care setting and can be used in patients requiring NIV. Many patients are underfed when receiving noninvasive ventilation therapies. HFNC may impair the swallowing ability and increase dysphagia while NIV may improve the swallowing reflexes. New technology preventing reflux and ensuring enteral feeding efficacy may increase the medical nutrition therapy safety and provide near-target energy and protein provision.

The patient requiring noninvasive ventilation presents one of the most challenging nutritional challenges. The main steps to improve nutrition administration are to assess nutritional status, evaluate the presence of dysphagia, choose the most adequate tool of respiratory support, and adapt nutritional therapy (oral, enteral, or parenteral) accordingly.
What Did the Ideal Beauty of the 15th Century Look Like? An Anthropometric Analysis of Botticelli Portraits
Authors: Jung Sung Gyun , Kim Hun , Hwang Kun , Hwang Young Joong
Published: June 2024

The aim of this study was to conduct an anthropometric analysis of the 5 portraits painted by Botticelli that depict Simonetta Vespucci. Five images in the Simonetta series by Botticelli workshop were measured. The anthropometric measurements of the face included 22 parameters on the lateral view (in 4 portraits; 18 distances and 4 angles) and 17 distances on the frontal view (in one portrait), which were measured using Adobe Photoshop. The absolute distances were calculated relative to the vertical corneal diameter (10.6 mm), which was calculated by multiplying the distance from the pupil’s center to the lower margin of the iris. In the lateral faces, the nasofrontal angle (g-n-prn) was 157.6±2.4 degrees, and the nasal tip angle (n-prn-sn) was 99.7±3.4 degrees. The nasolabial angle (prn-sn-ls) was 125.7±4.9 degrees, and the labiomental angle (li-sl-pg) was 131.6±4.4 degrees. The ratio of the upper lip height to the lower lip height (sn-sto/sto-sl) was 85.4±9.0%. The ratio of the upper lip vermillion to the upper lip height (ls-sto/sn-sto) was 27.7±3.9%. The ratio of the lower lip vermillion to the lower lip height (sto-li/sto-sl) was 47.2±6.6%. Comparing the data with 21st-century Italian females, forehead II height (tr-n), physiognomical face height (tr-gn), and morphologic face height (n-gn) of the beauties of the 15th century were significantly greater than those of 21st-century Italian females. However, there were no significant differences in lower face height (sn-gn) and nose height (n-sn). Considering the ongoing cultural relevance of Renaissance art, the esthetic proportions from this study may have reflection to the present day plastic surgery.
Comprehensive single cell transcriptomics analysis of murine osteosarcoma uncoversSkp2function in metastasis, genomic instability and immune activation and reveals additional target pathways
Authors: Ferrena Alexander , Zhang Ranxin , Wang Jichuan , Zheng Xiang Yu , Göker Barlas , Borjihan Hasibagan , Chae Sung-Suk , Lo Yungtai , Zhao Hongling , Schwartz Edward , Loeb David , Yang Rui , Geller David , Zheng Deyou , Hoang Bang
Published: June 2024

Osteosarcoma (OS) is the most common primary pediatric bone malignancy. One promising new therapeutic target isSKP2, encoding a substrate recognition factor of the SCF E3 ubiquitin ligase responsible for ubiquitination and proteasome degradation of substrate p27, thus driving cellular proliferation. We have shown previously that knockout ofSkp2in an immunocompetent transgenic mouse model of OS improved survival, drove apoptosis, and induced tumor inflammation. Here, we applied single-cell RNA-sequencing (scRNA-seq) to study primary OS tumors derived from Osx-Cre driven conditional knockout ofRb1andTrp53. We showed that murine OS models recapitulate the tumor heterogeneity and microenvironment complexity observed in patient tumors. We further compared this model with OS models with functional disruption ofSkp2: one withSkp2knockout and the other with the Skp2-p27 interaction disrupted (resulting in p27 overexpression). We found reduction of T cell exhaustion and upregulation of interferon activation, along with evidence of replicative and endoplasmic reticulum-related stress in theSkp2disruption models, and showed that interferon induction was correlated with improved survival in OS patients. Additionally, our scRNA-seq analysis uncovered decreased activities of metastasis-related gene signatures in theSkp2-disrupted OS, which we validated by observation of a strong reduction in lung metastasis in theSkp2knockout mice. Finally, we report several potential mechanisms of escape from targetingSkp2in OS, including upregulation ofMyctargets, DNA copy number amplification and overexpression of alternative E3 ligase genes, and potential alternative lineage activation. These mechanistic insights into OS tumor biology andSkp2function suggest novel targets for new, synergistic therapies, while the data and our comprehensive analysis may serve as a public resource for further big data-driven OS research.
STRAIGHTMORPH: A Voice Morphing Tool for Research in Voice Communication Sciences
Authors: Belin P , Kawahara H
Published: June 2024

The purpose of this paper is to make easily available to the scientific community an efficient voice morphing tool called STRAIGHTMORPH and provide a short tutorial on its use with examples. STRAIGHTMORPH consists of a set of Matlab functions allowing to generate high-quality, parametrically-controlled morphs of an arbitrary number of voice samples. A first step consists in extracting an ‘mObject’ for each voice sample, with accurate tracking of the fundamental frequency contour and manual definition of Time and Frequency anchors corresponding across samples to be morphed. The second step consists in parametrically combining the mObjects to generate novel synthetic stimuli, such as gender, identity or emotion continua, or random combinations. Although STRAIGHTMORPH has been designed for human voices it can work well with other types of sounds such as non-human primate vocalizations.
Integrating MHC Class I visibility targets into the ProteinMPNN protein design process
Authors: Gasser Hans-Christof , Oyarzún Diego A. , Alfaro Javier , Rajan Ajitha
Published: June 2024

ProteinMPNNis crucial in many protein design pipelines, identifying amino acid (AA) sequences that fold into given 3D protein backbone structures. We exploreProteinMPNNin the context of designing therapeutic proteins that need to avoid triggering unwanted immune reactions. More specifically, we focus on intra-cellular proteins that face the challenge of evading detection by Cytotoxic T-lymphocytes (CTLs) that detect their presence via the MHC Class I (MHC-I) pathway. To reduce visibility of the designed proteins to this immune-system component, we develop a framework that uses the large language model (LLM) tuning method, Direct Preference Optimization (DPO), to guideProteinMPNNin minimizing the number of predicted MHC-I epitopes in its designs. Our goal is to design proteins with low MHC-I immune-visibility while preserving the original structure and function. For our assessment, we first use AlphaFold to predict the 3D structures of designed protein sequences. We then use TM-score, that measures the structural alignment between the predicted design and original protein, to evaluate fidelity to the original protein structure. We find our LLM-based tuning method for constraining MHC-I visibility is able to effectively reduce visibility without compromising structural similarity to the original protein.
Horizontal transmission of functionally diverse transposons is a major source of new introns
Authors: Gozashti Landen , Nakamoto Anne , Russell Shelbi , Corbett-Detig Russell
Published: June 2024

Specialized transposable elements (TEs), introners, are one of the major drivers of intron gain in diverse eukaryotes. However, the molecular mechanism(s) and evolutionary processes driving introner propagation within and between lineages remain elusive. We analyze 8716 genomes, revealing 1093 introner families in 201 species spanning 1.7 billion years of evolution. Introners are derived from functionally diverse TEs including families of terminal-inverted-repeat DNA TEs, retrotransposons, cryptons, and helitrons as well as mobile elements with unknown molecular mechanisms. We identify eight cases where introners recently transferred between divergent host species, and show that giant viruses that integrate into genomes may facilitate introner transfer across lineages. We propose that intron gain is an inevitable consequence of TE activity in eukaryotic lineages, thereby resolving a key mystery of genome structure evolution.
Single-cell and spatial transcriptome characterize coinhibitory cell-cell communications during histological progression of lung adenocarcinoma
Authors: Hui Liu , Gao Qianman , Luo Judong
Published: June 2024

Lung adenocarcinoma, a prevalent and lethal malignancy globally, is characterized by significant tumor heterogeneity and a complex tumor immune microenvironment during its histologic pattern progression. Understanding the intricate interplay between tumor and immune cells is of paramount importance as it could potentially pave the way for the development of effective therapeutic strategies for lung adenocar-cinoma. In this study, we run comparative analysis of the single-cell transcriptomic data derived from tumor tissues exhibiting four distinct histologic patterns, lepidic, papillary, acinar and solid, in lung adeno-carcinoma. Our analysis unveiled several co-inhibitory receptor-ligand interactions, including PD1-PDL1, PVR-TIGIT and TIGIT-NECTIN2, that potentially exert a pivotal role in recruiting immunosuppressive cells such as M2 macrophages and Tregs into LUAD tumor, thereby establishing immunosuppressive microenvironment and inducing T cells to exhaustion state. Furthermore, The expression level of these co-inhibitory factors, such as NECTIN2 and PVR, were strongly correlated with low immune infiltration, unfavorable patient clinical outcomes and limited efficacy of immunotherapy. Furthermore, we conducted immunofluorescence assay and spatial transcriptomic sequencing to validated the spatial co-localization of typical co-inhibitory factors. We believe this study provides valuable insights into the heterogeneity of molecular, cellular interactions leading to immunosuppressive microenvironment during the histological progression of lung adenocarcinoma. The findings could facilitate the development of novel immunotherapy for lung cancer.