bluuebunny/crossref_metadata_2025 huggingface dataset:
Severe congenital neutropenia, SRP54 pathogenicity, and a framework for surveillance
Authors: Fan Elaine M. , Vagher Jennie , Meznarich Jessica A. , Ubico Erin Morales , Goteti Sasidhar , Peterson David , Rayes Ahmad , Maese Luke D.
Published: February 2023

Severe congenital neutropenia (SCN) is a rare disorder, often due to pathogenic variants in genes such as ELANE, HAX1, and SBDS. SRP54 pathogenic variants are associated with SCN and Shwachman‐Diamond‐like syndrome. Thirty‐eight patients with SRP54‐related SCN are reported in the literature. We present an infant with SCN, without classic Shwachman‐Diamond syndrome features, who presented with recurrent bacterial infections and an SRP54 (c.349_351del) pathogenic variant. Despite ongoing granulocyte colony‐stimulating factor therapy, this patient has no evidence of malignant transformation. Here we establish a framework for the future development of universal guidelines to care for this patient population.
Influence of landscape structure on previous exposure to Leptospira spp. and Brucella abortus in free‐living neotropical primates from southern Brazil
Authors: dos Santos Elisandro O. , Klain Vinícius F. , B. Manrique Sebastián , Rodrigues Rogério O. , dos Santos Helton F. , Sangioni Luís A. , Dasso Maurício G. , de Almeida Marco A. B. , dos Santos Edmilson , Born Lucas C. , Reck José , Botton Sônia de Avila
Published: February 2023

The environments in which neotropical primates live have been undergoing an intense fragmentation process, constituting a major threat to the species' survival and causing resource scarcity, social isolation, and difficulty in dispersal, leaving populations increasingly vulnerable. Moreover, the proximity of wild environments to anthropized landscapes can change the dynamics of pathogens and the parasite‐host‐environment relationship, creating conditions that favor exposure to different pathogens. To investigate the previous exposure of free‐living primates in Rio Grande do Sul State (RS), southern Brazil, to the bacterial agents Leptospira spp. and Brucella abortus, we investigated agglutinating antibodies against 23 serovars of Leptospira spp. using the microscopic agglutination test and B. abortus acidified antigen test in primate serum samples; 101 samples from primates captured between 2002 and 2016 in different forest fragments were used: 63 Alouatta caraya, 36 Alouatta guariba clamitans, and 02 Sapajus nigritus cucullatus. In addition, the forest remnants where the primates were sampled were characterized in a multiscale approach in radii ranging from 200 to 1400 m to investigate the potential relationship of previous exposure to the agent with the elements that make up the landscape structure. The serological investigation indicated the presence of antibodies for at least one of the 23 serovars of Leptospira spp. in 36.6% (37/101) of the samples analyzed, with titers ranging from 100 to 1600. The most observed serovars were Panama (17.8%), Ballum (5.9%), Butembo (5.9%), Canicola (5.9%), Hardjo (4.9%), and Tarassovi (3.9%); no samples were seropositive for Brucella abortus. Decreased forest cover and edge density were the landscape factors that had a significant relationship with Leptospira spp. exposure, indicating that habitat fragmentation may influence contact with the pathogen. The data generated in this study demonstrate the importance of understanding how changes in landscape structure affect exposure to pathogenic microorganisms of zoonotic relevance. Hence, improving epidemiological research and understanding primates' ecological role in these settings can help improve environmental surveillance and conservation strategies for primate populations in different landscapes.
Homo medicus: The transition to meat eating increased pathogen pressure and the use of pharmacological plants in Homo
Authors: Hagen Edward H. , Blackwell Aaron D. , Lightner Aaron D. , Sullivan Roger J.
Published: February 2023

The human lineage transitioned to a more carnivorous niche 2.6 mya and evolved a large body size and slower life history, which likely increased zoonotic pathogen pressure. Evidence for this increase includes increased zoonotic infections in modern hunter‐gatherers and bushmeat hunters, exceptionally low stomach pH compared to other primates, and divergence in immune‐related genes. These all point to change, and probably intensification, in the infectious disease environment of Homo compared to earlier hominins and other apes. At the same time, the brain, an organ in which immune responses are constrained, began to triple in size. We propose that the combination of increased zoonotic pathogen pressure and the challenges of defending a large brain and body from pathogens in a long‐lived mammal, selected for intensification of the plant‐based self‐medication strategies already in place in apes and other primates. In support, there is evidence of medicinal plant use by hominins in the middle Paleolithic, and all cultures today have sophisticated, plant‐based medical systems, add spices to food, and regularly consume psychoactive plant substances that are harmful to helminths and other pathogens. We propose that the computational challenges of discovering effective plant‐based treatments, the consequent ability to consume more energy‐rich animal foods, and the reduced reliance on energetically‐costly immune responses helped select for increased cognitive abilities and unique exchange relationships in Homo. In the story of human evolution, which has long emphasized hunting skills, medical skills had an equal role to play.
Placental growth factor as a sensitive biomarker for vascular cognitive impairment
Authors: Hinman Jason D. , Elahi Fanny , Chong Davis , Radabaugh Hannah , Ferguson Adam , Maillard Pauline , Thompson Jeffrey F , Rosenberg Gary A. , Sagare Abhay , Moghekar Abhay , Lu Hanzhang , Lee Tiffany , Wilcock Donna , Satizabal Claudia L. , Tracy Russell , Seshadri Sudha , Schwab Kristin , Helmer Karl , Singh Herpreet , Kivisäkk Pia , Greenberg Steve , DeCarli Charlie , Kramer Joel
Published: February 2023

INTRODUCTION

High‐performing biomarkers measuring the vascular contributions to cognitive impairment and dementia are lacking.

METHODS

Using a multi‐site observational cohort study design, we examined the diagnostic accuracy of plasma placental growth factor (PlGF) within the MarkVCID Consortium (n = 335; CDR 0‐1). Subjects underwent clinical evaluation, cognitive testing, MRI, and blood sampling as defined by Consortium protocols.

RESULTS

In the prospective population of 335 subjects (72.2 ± 7.8 years of age, 49.3% female), plasma PlGF (pg/mL) shows an ordinal odds ratio (OR) of 1.16 (1.07‐1.25; P = .0003) for increasing Fazekas score and ordinal OR of 1.22 (1.14‐1.32; P < .0001) for functional cognitive impairment measured by the Clinical Dementia Rating scale. We achieved the primary study outcome of a site‐independent association of plasma PlGF (pg/mL) with white matter injury and cognitive impairment in two of three study cohorts. Secondary outcomes using the full MarkVCID cohort demonstrated that plasma PlGF can significantly discriminate individuals with Fazekas ≥ 2 and CDR = 0.5 (area under the curve [AUC] = 0.74) and CDR = 1 (AUC = 0.89) from individuals with CDR = 0.

DISCUSSION

Plasma PlGF measured by standardized immunoassay functions as a stable, reliable, diagnostic biomarker for cognitive impairment associated with substantial white matter burden.
Permissive untreated pseudoaneurysm concept in damage control interventional radiology for traumatic pancreaticoduodenal artery injury
Authors: Yonemitsu Takafumi , Shibata Naoaki , Shima Nozomu , Fuchigami Junya , Miyake Yuichi , Ikoma Akira , Minamiguchi Hiroki , Sonomura Tetsuo , Kato Seiya
Published: February 2023

Background

Angioembolization for traumatic pancreaticoduodenal artery injury with unstable circulation, which characteristically requires a prolonged procedure time, does not yet have a standardized strategy for damage control interventional radiology.

Case Presentation

We encountered two cases of rare traumatic pancreaticoduodenal artery injury wherein the patients were saved by a multidisciplinary team with a shared goal of clinical success, rather than the procedural success of angioembolization. Both patients treated with angioembolization had residual pseudoaneurysm or faint extravasation in the pancreaticoduodenal artery arcade. We prioritized critical care with preemptive plasma transfusion and aggressive blood pressure control, and planned repeat angiography. The patients showed no clinical signs of rebleeding or pseudoaneurysm based on computed tomography during follow‐up.

Conclusion

Our findings suggest that the permissive untreated pseudoaneurysm concept can be useful in developing damage control interventional radiology strategies for trauma cases with challenging time limitations, such as traumatic pancreaticoduodenal artery injury with circulatory collapse.
Chemoenzymatic Late‐Stage Modifications Enable Downstream Click‐Mediated Fluorescent Tagging of Peptides
Authors: Colombano Alessandro , Dalponte Luca , Dall'Angelo Sergio , Clemente Claudia , Idress Mohannad , Ghazal Ahmad , Houssen Wael E.
Published: February 2023

Aromatic prenyltransferases from cyanobactin biosynthetic pathways catalyse the chemoselective and regioselective intramolecular transfer of prenyl/geranyl groups from isoprene donors to an electron‐rich position in these macrocyclic and linear peptides. These enzymes often demonstrate relaxed substrate specificity and are considered useful biocatalysts for structural diversification of peptides. Herein, we assess the isoprene donor specificity of the N1‐tryptophan prenyltransferase AcyF from the anacyclamide A8P pathway using a library of 22 synthetic alkyl pyrophosphate analogues, of which many display reactive groups that are amenable to additional functionalization. We further used AcyF to introduce a reactive moiety into a tryptophan‐containing cyclic peptide and subsequently used click chemistry to fluorescently label the enzymatically modified peptide. This chemoenzymatic strategy allows late‐stage modification of peptides and is useful for many applications.
Reductive Asymmetric Aza‐Mislow‐Evans Rearrangement by 1,3,2‐Diazaphospholene Catalysis**
Authors: Zhang Guoting , Cramer Nicolai
Published: February 2023

1,3,2‐diazaphospholene hydrides (DAP−H) enable smooth conjugate reduction of polarized double bonds. The transiently formed phosphorus‐enolate provides a potential platform for reductive α‐functionalizations. In this respect, asymmetric C‐heteroatom bond forming processes are synthetically appealing but remain elusive. We report a 1,3,2‐diazaphospholene‐catalyzed three‐step cascade reaction of N‐sulfinyl acrylamides comprised of conjugate reduction, [2,3]‐sigmatropic aza‐Mislow‐Evans rearrangement and subsequent S−O bond cleavage. The obtained enantio‐enriched α‐hydroxy amides are formed in good yields and excellent enantiospecificity. The stereo‐defined P‐bound N,O‐ketene aminal ensures an excellent transfer of chirality from the sulfur stereocenter to α‐carbon. The transformation operates under mild conditions at ambient temperature. Moreover, DAP−H is a competent reductant for the cleavage of formed sulfenate ester, eliminating the extra step in traditional Mislow‐Evans processes.
Chemoselective 1,2‐Reduction and Regiodivergent Deuteration of Chromium‐Bound Arenes
Authors: Qiu Jia‐Yi , Zeng Wei‐Long , Xie Hui , Wang Ming‐Yang , Li Wei
Published: February 2023

Herein, a general strategy for chemo‐ and regioselective 1,2‐reduction of chromium‐bound arenes was developed, thus providing rapid access to 1,3‐cyclohexadienes. Selective arene activation via π‐complexation along with the use of mild hydride Ph3SiH can overcome the inherently low reactivity of arene π‐bonds while tolerating various reduction‐sensitive functional groups. Its versatility further enables a regiodivergent deuteration. Using different sequences of (non)deuterated hydride and acid reagents, the deuterated positions as well as the degrees of deuterium incorporation can be controlled precisely, which leads to a large and previously inaccessible chemical space for 1,3‐cyclohexadiene isotopologues. A reasonable mechanism was proposed based on intermediate capture and control experiments. The synthetic value of this selective 1,2‐reduction was demonstrated in the formal total synthesis of (±)‐galanthamine and (±)‐lycoramine.
The effects of surface modified date‐palm fiber fillers upon the thermo‐physical performances of high density polyethylene‐polyvinyl chloride blend with maleic anhydride as a grafting agent
Authors: Maou Samira , Meftah Yazid , Grohens Yves , Kervoelen Antoine , Magueresse Anthony
Published: February 2023

To demonstrate the upcycling of thermoplastic waste with good thermo‐physical properties, high density polyethylene (HDPE; 80 phr) and polyvinyl chloride (PVC; 20 phr) are mixed as the matrix using maleic anhydride (MAH) reinforced with unmodified and modified date palm fibers (DPFs; 30 phr). The effects of in situ grafting of MAH onto the DPFs‐HDPE‐PVC composites upon the resultant thermo‐physical characteristics are investigated and analyzed via Fourier transform infrared spectroscopy and scanning electron microscopy. Thus, the effective compatibilizing of both the HDPE‐PVC component and the grafted HDPE‐PVC blend with the modified DPFs are confirmed. In addition, the results of dynamical mechanical analysis and differential scanning calorimetry indicate that the glass transition temperature (Tg) of the composite is enhanced by the incorporation of modified DPFs. The thermal, mechanical, and water uptake properties of the composites are also improved. Rheological analysis at low frequency reveals that the introduction of hydrolyzed DPFs results in a higher complex viscosity (1.94 × 106 Pa s) and storage modulus (119,844 MPa) for the obtained composite (designated G‐Hydro). Overall, the G‐Hydro composite exhibits the best performance, making it ideal for a variety of construction and building purposes.
Terminal 3 Flughafen Frankfurt – Neubau der Brücke Vorfahrtstisch T3
Authors: Weißer Ingo , Diefenhardt Christopher , Dederichs Jens , Romanowski Jascha
Published: February 2023

Der Flughafen Frankfurt wächst. Im Süden des Frankfurter Airports wird derzeit das neue Terminal 3 mit drei Flugsteigen und zugehöriger Infrastruktur errichtet. Im Zusammenhang mit diesem Großprojekt steht der sog. Vorfahrtstisch vor dem künftigen Terminalhauptgebäude – ein 580 m langes Brückenbauwerk zur Anbindung des Check‐in‐Bereichs. Die Brücke weist hohe architektonische Anforderungen und komplizierte Geometrien auf, die besondere Lösungsansätze in der Planungs‐ und Ausführungsphase erforderten.
Evaluation of preferred binding regions on ubiquitin and IgG1 FC for interacting with multimodal cation exchange resins using DEPC labeling/mass spectrometry
Authors: Dhingra Kabir , Gudhka Ronak B. , Cramer Steven M.
Published: February 2023

There is significant interest in identifying the preferred binding domains of biological products to various chromatographic materials. In this work, we develop a biophysical technique that uses diethyl pyrocarbonate (DEPC) based covalent labeling in concert with enzymatic digestion and mass spectrometry to identify the binding patches for proteins bound to commercially available multimodal (MM) cation exchange chromatography resins. The technique compares the changes in covalent labeling of the protein in solution and in the bound state and uses the differences in this labeling to identify residues that are sterically shielded upon resin binding and, therefore, potentially involved in the resin binding process. Importantly, this approach enables the labeling of many amino acids and can be carried out over a pH range of 5.5–7.5, thus enabling the protein surface mapping at conditions of interest in MM cation exchange systems. The protocol is first developed using the model protein ubiquitin and the results indicate that lysine residues located on the front face of the protein show dramatic changes in DEPC labeling while residues present on other regions have minimal or no reductions. This indicates that the front face of ubiquitin is likely involved in resin binding. In addition, surface property maps indicate that the hypothesized front face binding region consists of overlapping positively charged and hydrophobic patches. The technique is then employed with an IgG1 FC and the results indicate that residues on the CH2–CH3 interface and the hinge are significantly sterically shielded upon binding to the resin. Further, these regions are again associated with significant overlap of positively charged and hydrophobic patches. On the other hand, while, residues on the CH2 and the front face of the IgG1 FC also exhibited some changes in DEPC labeling upon binding, these regions have less distinct charged and hydrophobic patches. Importantly, the hypothesized binding patches identified for both ubiquitin and FC using this approach are shown to be consistent with previously reported NMR studies. In contrast to NMR, this new approach enables the identification of preferred binding regions without the need for isotopically labeled proteins or chemical shift assignments. The technique developed in this work sets the stage for the evaluation of the binding domains of a wide range of biological products to chromatographic surfaces, with important implications for designing biomolecules with improved biomanufacturability properties.
Sustainability trade‐offs in the circular economy: A maturity‐based framework
Authors: Ünal Enes , Sinha Vikash Kumar
Published: February 2023

The theoretical and practical understanding of sustainability implementation has been changing in depth and scope. In particular, circular economy paradigms (e.g., Cradle to Cradle or “C2C” practices) have enabled firms to rethink their resource management behavior, resulting in distinct trade‐off patterns among different sustainability dimensions. Furthermore, while many established firms remain reactive and market‐oriented in their sustainability implementations, sustainability‐rooted firms proactively integrate sustainability practices into their core business. The prior literature on sustainability trade‐offs has unduly focused more on established firms that predominantly indulge in market‐oriented decisions and trade‐offs between profit and sustainability, lacking insights into the approaches adopted by sustainability‐rooted firms and trade‐offs among the different dimensions of sustainability. We performed a mixed‐methods study to address this gap and illustrated the rationale and dynamics of trade‐offs among five sustainability dimensions (i.e., material health, material reutilization, renewable energy, water stewardship, and social fairness). We primarily focused on firms in the United States and the European Union since they are the leading areas in terms of circular economy adoption. We explained the pattern of sustainability trade‐offs and associated them with a three‐stage maturity framework, namely, low‐hanging fruits, exploratory, and resource and time intensive. We contributed to the theory by depicting the influence of resource allocation and sustainability maturity level on trade‐offs among the five dimensions of sustainability. Practitioners can leverage our framework to better understand their sustainability transformation and make more informed decisions for attaining higher levels of sustainability with more impact.
Indirect co‐culture of islet cells in 3D biocompatible collagen/laminin scaffold with angiomiRs transfected mesenchymal stem cells
Authors: Sabet Sarvestani Fatemeh , Tamaddon Ali‐Mohammad , Yaghoobi Ramin , Geramizadeh Bita , Abolmaali Samira Sadat , Kaviani Maryam , Keshtkar Somayeh , Pakbaz Sara , Azarpira Negar
Published: February 2023

Diabetes is an autoimmune disease in which the pancreatic islets produce insufficient insulin. One of the treatment strategies is islet isolation, which may damage these cells as they lack vasculature. Biocompatible scaffolds are one of the efficient techniques for dealing with this issue. The current study is aimed to determine the effect of transfected BM‐MSCS with angiomiR‐126 and ‐210 on the survival and functionality of islets loaded into a 3D scaffold via laminin (LMN). AngiomiRs/Poly Ethylenimine polyplexes were transfected into bone marrow‐mesenchymal stem cells (BM‐MSCs), followed by 3‐day indirect co‐culturing with islets laden in collagen (Col)‐based hydrogel scaffolds containing LMN. Islet proliferation and viability were significantly increased in LMN‐containing scaffolds, particularly in the miRNA‐126 treated group. Insulin gene expression was superior in Col scaffolds, especially, in the BM‐MSCs/miRNA‐126 treated group. VEGF was upregulated in the LMN‐containing scaffolds in both miRNA‐treated groups, specifically in the miRNA‐210, leading to VEGF secretion. MiRNAs' target genes showed no downregulation in LMN‐free scaffolds; while a drastic downregulation was seen in the LMN‐containing scaffolds. The highest insulin secretion was recorded in the Oxidized dextran (Odex)/ColLMN+ group with miRNA‐126. LMN‐containing biocompatible scaffolds, once combined with angiomiRs and their downstream effectors, promote islets survival and restore function, leading to enhanced angiogenesis and glycemic status.
Photophysical Behavior of Self‐Organizing Derivatives of 10‐ and 12‐Vertex p‐Carboranes, and their Bicyclo[2.2.2]octane and Benzene Analogues
Authors: Jakubowski Rafał , Januszko Adam , William Tilford R. , Radziszewski George J. , Pietrzak Anna , Young Victor G. , Kaszyński Piotr
Published: February 2023

Four series of isostructural derivatives of 3‐ring liquid crystalline derivatives containing p‐carboranes (12‐vertex A, and 10‐vertex B), bicyclo[2.2.2]octane (C), or benzene (D) as the variable structural element were investigated for their mesogenic behavior and electronic interactions. Comparative studies demonstrated that the effectiveness of elements A–D in stabilization of the mesophase typically increases in the order: B<A<C<D. Absorption and emission spectroscopy for the four series and reference compounds augmented with DFT computational results revealed that the degree of electronic interactions with the connected benzene π system increases in the order C<A<B<D. Emission spectra exhibit large Stokes’ shifts for 10‐vertex derivatives (B) in solutions and in the solid state. Spectroscopic characterization was supplemented with polarization electronic spectroscopy and solvatochromic studies of selected series. Overall, 12‐vertex p‐carborane A acts as an electron withdrawing auxochromic substituent with interactions similar to those of bicyclo[2.2.2]octane, although capable of accepting some electron density in the excited state. In contrast, 10‐vertex p‐carborane B is much more interactive with the π‐aromatic electron manifold and exhibits greater ability to participate in photo‐induced CT processes. Absorption and emission energies and quantum yields (1‐51 %) for carborane derivatives, representing the D−A−D system, were compared to those of their isoelectronic zwitterionic analogues (the A−D−A system). The analysis is supplemented with four single‐crystal XRD structures.
Rationalizing the Extent of the “Sergeants‐and‐Soldiers” Effect in Supramolecular Helical Catalysts: Effect of Copper Coordination
Authors: Hammoud Ahmad , Li Yan , Martínez‐Aguirre Mayte A. , Kong Huanjun , Dubreucq Ludovic , Troufflard Claire , Bouteiller Laurent , Raynal Matthieu
Published: February 2023

Aggregation of supramolecular helices, for example through interdigitation of their alkyl side chains or through more directional supramolecular interactions, leads to hierarchical architectures with original structural and chiroptical properties. However, when a chiral monomer (the “sergeant”) is introduced as a minor component in these assemblies composed of a majority of achiral monomers (the “soldiers”), it is not clear how the aggregation changes the ability of the sergeant to induce a preferential helicity to the polymer main chain (the so‐called “sergeants‐and‐soldiers” effect). This study reports a detailed investigation of the influence of [Cu(OAc)2⋅H2O] coordination on the structure and chiroptical properties of helical hydrogen‐bonded co‐assemblies composed of a catalytically‐active benzene‐1,3,5‐tricarboxamide (BTA) monomer, acting as the “soldier”, and an enantiopure BTA monomer derived from cyclohexylalanine, playing the role of the “sergeant”. The copper actually significantly influences the extent of the “sergeants‐and‐soldiers” effect since it acts as a crosslink that induces some chiral defects in the supramolecular helices. These crosslinks appear to be preserved during the catalytic hydrosilylation of 4‐nitroacetophenone. The aggregation of helices through the formation of copper crosslinks is reversible since homochiral single helices are exclusively formed in the case of sergeant‐rich assemblies. The fact that both main chain and side chain aggregation affects the chiroptical properties of supramolecular helices must be considered in the design of elaborated chiral materials.
Specific Signal Enhancement on an RNA–Protein Interface by Dynamic Nuclear Polarization
Authors: Aladin Victoria , Sreemantula Arun K. , Biedenbänder Thomas , Marchanka Alexander , Corzilius Björn
Published: February 2023

Invited for the cover of this issue are the groups of Alexander Marchanka at the Leibniz University of Hannover and Björn Corzilius at the University of Rostock. The image depicts the local generation of nuclear spin hyperpolarization, which selectively “illuminates” the interaction surface of a ribonuclear protein complex for solid‐state NMR spectroscopy. Read the full text of the article at 10.1002/chem.202203443.
Artificial intelligence and digital biomarker in precision pathology guiding immune therapy selection and precision oncology
Authors: Huss Ralf , Raffler Johannes , Märkl Bruno
Published: February 2023

Background

The currently available immunotherapies already changed the strategy how many cancers are treated from first to last line. Understanding even the most complex heterogeneity in tumor tissue and mapping the spatial cartography of the tumor immunity allows the best and optimized selection of immune modulating agents to (re‐)activate the patient's immune system and direct it against the individual cancer in the most effective way.

Recent Findings

Primary cancer and metastases maintain a high degree of plasticity to escape any immune surveillance and continue to evolve depending on many intrinsic and extrinsic factors In the field of immune‐oncology (IO) immune modulating agents are recognized as practice changing therapeutic modalities. Recent studies have shown that an optimal and lasting efficacy of IO therapeutics depends on the understanding of the spatial communication network and functional context of immune and cancer cells within the tumor microenvironment. Artificial intelligence (AI) provides an insight into the immune‐cancer‐network through the visualization of very complex tumor and immune interactions in cancer tissue specimens and allows the computer‐assisted development and clinical validation of such digital biomarker.

Conclusions

The successful implementation of AI‐supported digital biomarker solutions guides the clinical selection of effective immune therapeutics based on the retrieval and visualization of spatial and contextual information from cancer tissue images and standardized data. As such, computational pathology (CP) turns into “precision pathology” delivering individual therapy response prediction. Precision Pathology does not only include digital and computational solutions but also high levels of standardized processes in the routine histopathology workflow and the use of mathematical tools to support clinical and diagnostic decisions as the basic principle of a “precision oncology”.
A Bioequivalence Study With Pharmacokinetic Endpoints for Azithromycin Eye Drops
Authors: Wu Feng , Zhao Xiuli , Guo Shaojie , Ni Siyang , Dai Yuyang , Han Ying , Ma Ke , Wang Yunzhe
Published: February 2023

Azithromycin eye drops with a bioadhesive ocular drug‐delivery system can offer a simplified dosing regimen. In this study, we compared the pharmacokinetic properties and assessed the bioequivalence of a newly developed generic azithromycin eye drop with a branded formulation. This open‐label, single‐dose, randomized, crossover, sparse‐sampling ocular bioequivalence study was conducted on 48 healthy Chinese volunteers. Tear samples were collected for up to 36 hours, and each participant was randomly allocated to one of the prespecified sampling times. Tear drug concentrations were determined using a validated liquid chromatography‐tandem mass spectrometry method. The pharmacokinetic parameters were calculated via noncompartmental analysis. A nonparametric bootstrap method was used to obtain 90% confidence intervals (CIs) for the ratios of the test and reference drugs. Tolerability was evaluated for adverse events (AEs). After bootstrapping (1000 iterations), the 90%CIs for the log‐transformed ratios of Cmax, AUC0‐t, and AUC0–∞were within the acceptable bioequivalence range (80%–125%). No moderate‐to‐severe AEs were reported for either formulation. Bioequivalence was demonstrated between the two formulations. The sparse‐sampling design with the bootstrapping technique is promising for bioequivalence studies of topical ophthalmic drugs.
Vibrationally Resolved Inner‐Shell Photoexcitation of the Molecular Anion C2−
Authors: Schippers S. , Hillenbrand P.‐M. , Perry‐Sassmannshausen A. , Buhr T. , Fuchs S. , Reinwardt S. , Trinter F. , Müller A. , Martins M.
Published: February 2023

Carbon 1s core‐hole excitation of the molecular anion C2− has been experimentally studied at high resolution by employing the photon‐ion merged‐beams technique at a synchrotron light source. The experimental cross section for photo–double‐detachment shows a pronounced vibrational structure associated with
and
core excitations of the C2− ground level and first excited level, respectively. A detailed Franck‐Condon analysis reveals a strong contraction of the C2− molecular anion by 0.2 Å upon this core photoexcitation. The associated change of the molecule's moment of inertia leads to a noticeable rotational broadening of the observed vibrational spectral features. This broadening is accounted for in the present analysis which provides the spectroscopic parameters of the C2−
and
core‐excited levels.
From bedside to bench: how existing therapies inform the relationship between Epstein–Barr virus and multiple sclerosis
Authors: Dyer Zoe , Tscharke David , Sutton Ian , Massey Jennifer
Published: February 2023

Therapy for relapsing–remitting multiple sclerosis (MS) has advanced dramatically despite incomplete understanding of the cause of the condition. Current treatment involves inducing broad effects on immune cell populations with consequent off‐target side effects, and no treatment can completely prevent disability progression. Further therapeutic advancement will require a better understanding of the pathobiology of MS. Interest in the role of Epstein–Barr virus (EBV) in multiple sclerosis has intensified based on strong epidemiological evidence of an association between EBV seroprevalence and MS. Hypotheses proposed to explain the biological relationship between EBV and MS include molecular mimicry, EBV immortalised autoreactive B cells and infection of glial cells by EBV. Examining the interaction between EBV and immunotherapies that have demonstrated efficacy in MS offers clues to the validity of these hypotheses. The efficacy of B cell depleting therapies could be consistent with a hypothesis that EBV‐infected B cells drive MS; however, loss of T cell control of B cells does not exacerbate MS. A number of MS therapies invoke change in EBV‐specific T cell populations, but pathogenic EBV‐specific T cells with cross‐reactivity to CNS antigen have not been identified. Immune reconstitution therapies induce EBV viraemia and expansion of EBV‐specific T cell clones, but this does not correlate with relapse. Much remains unknown regarding the role of EBV in MS pathogenesis. We discuss future translational research that could fill important knowledge gaps.
Low 25 (OH) vitamin D levels are associated with increased prevalence of nonalcoholic fatty liver disease and significant liver fibrosis
Authors: Ciardullo Stefano , Muraca Emanuele , Cannistraci Rosa , Perra Silvia , Lattuada Guido , Perseghin Gianluca
Published: February 2023

Aims

Evidence on the role of 25‐Hydroxyvitamin D (25(OH)D) in the occurrence and progression of nonalcoholic fatty liver disease (NAFLD) is conflicting and population‐based data are scarce. Here, we assess the association between 25(OH)D levels, NAFLD and liver fibrosis in the general population.

Materials and Methods

This is an analysis of data from the 2017–2018 cycle of the National Health and Nutrition Examination Survey. We included adult participants with available data on vibration‐controlled transient elastography (VCTE) and without viral hepatitis and significant alcohol consumption. Steatosis and fibrosis were diagnosed by the median values of controlled attenuation parameter (CAP) and liver stiffness measurement (LSM), respectively. 25(OH)D was measured by high performance liquid chromatography‐tandem mass spectrometry.

Results

A total of 3970 participants (1928 men and 2042 women) were included in the study. The prevalence of NAFLD (CAP ≥ 274 dB/m) and significant liver fibrosis (LSM ≥ 8 kPa) were 41.7% (95% CI 39.4–44.0) and 8.4% (95% CI 7.0–9.9), respectively, while 21.1% (95% CI 17.3–25.4) of participants had low 25(OH)D levels (<50 nmol/L). A multivariable logistic regression model adjusted for age, sex, race‐ethnicity, body mass index, waist circumference, calendar period, diabetes, chronic kidney disease, and vitamin D supplementation showed that compared with participants with low 25(OH)D, those with optimal levels (≥75 nmol/L) had lower odds of both NAFLD (OR 0.73, 95% CI 0.55–0.98 p = 0.038) and significant liver fibrosis (OR 0.65, 95% CI 0.44–0.96, p = 0.033).

Conclusions

An inverse relationship was found between 25(OH)D and NAFLD and fibrosis, suggesting a possible role of vitamin D in NAFLD occurrence and progression.
Taurodeoxycholate, a GPCR19 agonist, ameliorates atopic dermatitis in Balb/c mice
Authors: Ghaderpour Aziz , Jeong Ju‐Young , Kim Youn‐Hee , Zou Yunyun , Park Kyung‐Sun , Hong Eun‐Ji , Koh Young‐Jae , Seong Seung‐Yong
Published: February 2023

Keratinocytes are pivotal cells in the pathogenesis of atopic dermatitis (AD) as much as Th2 cells. In this sense, regulation of pro‐inflammatory features of keratinocytes might be useful for AD patients. P2X7R‐mediated activation of NLRP3 inflammasome (N3I) in keratinocytes and myeloid cells plays crucial roles in AD. Nonetheless, inhibition of P2X7R has not been feasible because of polymorphisms and ubiquitous expression of P2X7R. Here, we report that GPCR19 colocalizes with P2X7R, and a GPCR19 agonist (taurodeoxycholate [TDCA]) inhibits the activation of P2X7R. Noncistronically, TDCA inhibits NF‐kB activation via the adenylate cyclase‐PKA pathway and BzATP‐mediated Ca++ mobilization. Cistronically, TDCA suppresses the expression of P2X7R and N3I components in keratinocytes. NLRP3 oligomerization and the production of mature IL‐1β and IL‐18 was suppressed by TDCA treatment in keratinocytes. Topical TDCA treatment ameliorates proinflammatory features of AD in mice induced by DNCB, MC903, or oxazolone. Taken together, a GPCR19 agonist such as TDCA might inhibit P2X7R‐mediated N3I activation of keratinocytes, which is crucial for the pathogenesis of AD.
Nitric Oxide Disproportionation Mediated by a Rh Complex with an Asymmetric Pincer Ligand: Spectroscopic Detection of a Dinitrosyl Intermediate
Authors: Gallego Cecilia M. , Ben‐David Yehoshoa , Milstein David , Doctorovich Fabio , Pellegrino Juan
Published: February 2023

The disproportionation of nitric oxide was studied by FTIR with two different Rh(I)PCN complexes as mediators (PCN 1‐((diethylamino)methyl)‐3‐((di‐tertbutylphosphino)methyl)‐benzene). As had already been reported for a PCP analogue, reaction yielded a Rh(PCN)(NO)(NO2) complex along with gaseous N2O in both cases. However, when [Rh(PCN)(NO)]⋅ was used as a reactant, FTIR monitoring allowed for the detection of signals of a reaction intermediate, coherent with the expected but seldom reported dinitrosyl species Rh(PCN)(NO)(NO). DFT studies on this species revealed that pincer hemilability of the amino arm is involved in its stabilization, therefore accounting for the differences observed in reactivity between PCN and PCP.
Exergy, Exergoeconomic, Exergoenvironmental Analysis and Working Fluid Picking of an Integrated Liquefied Natural Gas Cold Energy Utilization System Consisting of an Organic Rankine Cycle and Two‐Stage Turbine Organic Flash Cycle
Authors: Guo Yuanyuan , Wang Xiao , Liu Dejun
Published: February 2023

A novel integrated system is suggested herein to recover liquefied natural gas (LNG) cold energy more reasonably and effectively, containing an organic Rankine cycle (ORC), a two‐stage turbine organic flash cycle (TTOFC), and an LNG expansion cycle. R134a‐R32, R134a‐Propylene, R152a‐Propylene, and R152a‐R32 are picked as the working fluid combinations for the system. A comprehensive study, including the net outpower power, exergy, exergoeconomic, and exergoenvironmental analysis, is conducted. The effects of the turbine 1 inlet temperature, the ORC working fluid mass flow in the heat exchanger 3, the pump 5 outlet pressure, and the inlet pressure for the flash tank in the TTOFC on the performance of the above three criteria are presented. The NSGA‐II method is used for three‐objective optimization and another design with ORC and single‐stage turbine organic flash cycle is set to compare with the new combined cooling, heating, and power system. The results show that R134a‐R32 is the best combination. In the R134a‐R32 combination, the total capital cost is 25.64 $ h−1, and the total environmental impact is 53.75 mPts h−1.
Coevolution mechanism and branch of pillar‐overburden fissures in shallow coal seam mining
Authors: Zhang Jie , He Yifeng , Yang Tao , Bai Wenyong , Wu Jianjun , Zhuo Qingsong , Gao Shoushi
Published: February 2023

The large‐scale mining of coal resources promotes the formation of section coal pillar groups between working faces. The overlying strata are supported by coal pillars, which leads to the formation of a unique fracture‐bearing structure in the key stratum, resulting in the evolution of fissures (cracks) and a generally high load on the supports. Studying the fracture‐bearing structure formed by coal pillars and overlying strata (fissures) is the basis for realizing rational mining of working faces. Here, the evolution characteristics of coal pillar‐overburden rock (fissures) in shallow coal seam mining and the working resistance of the support with stable fracture bearing structure of section coal pillar and overburden rock were studied in the No. 1‐2 coal mining of Longhua Coal Mine in Shenmu City, Northern Shaanxi. The fissure evolution characteristics on both sides of the coal pillar and the fracture‐bearing structure of the rock stratum were obtained by physical similarity simulation experiment. The mechanical calculation model of the coal pillar‐overburden rock (fissure) structure was established by theoretical derivation and calculation, and the working resistance of advanced support with a stable mechanical structure was studied. The research shows that the fracture evolution and rock fracture characteristics of a shallow coal seam mining face can be divided into three zones. Through the reanalysis of the mechanical structure of coal pillar‐overburden rock (fissure), the combined mechanical structure of the subkey stratum consisting of a lagging broken step rock beam structure and the main key stratum consisting of a hinged rock beam structure was obtained. Combined with the failure characteristics of the section coal pillar, a mechanical structure calculation method suitable for the bearing characteristics of section coal pillar support in shallow coal buried layers was obtained, and the field measurement results were verified.
Geostatistical and geoarchaeological study of Holocene floodplains and site distributions on the Sha‐Ying River Basin, Central China
Authors: Zhang Hai , Li Wei , Bevan Andrew , Wang Hui , Liang Fawei , Cao Yanpeng , Zhuang Yijie
Published: February 2023

Geostatistics has become a powerful method for investigating complex spatial variations of prehistoric settlements in floodplains and other geomorphological settings. A geoarchaeological drilling program that covers most of the Sha‐Ying River Basin provides a rare opportunity with unusually detailed environmental data to contest and develop the geostatistics method, which proves to be essential, in combination with archaeological data, to understand long‐term (9000–2500 B.P.) patterns of human inhabitation and adaption to volatile floodplain environments in eastern Central China. We analysed the variography and multivariate ordination of the borehole data and explored the complexities of landform evolution, with reference to sedimentation processes and soil development in the floodplain of the Sha‐Ying River. The recurrent impact of river floods on regional landforms is manifested by spatial‐autocorrelated properties over distances up to 10 km, sometimes with directional trends. We then developed a model of landform evolution through kriging and compared the model with detailed reconstruction of archaeological settlement patterns. Our results illustrate long‐term socio‐environmental dynamics by which human communities first populated and then adapted in diverse ways to the changing floodplain environments from the early to middle Holocene. This improved method will have far‐reaching implications for future studies on similar geomorphological settings across vast floodplains of Central China and other global regions.
Predictive value of clinical and radiomic features for radiation therapy response in patients with lymph node‐positive head and neck cancer
Authors: Franzese Ciro , Lillo Sara , Cozzi Luca , Teriaca Maria Ausilia , Badalamenti Marco , Di Cristina Luciana , Vernier Veronica , Stefanini Sara , Dei Damiano , Pergolizzi Stefano , De Virgilio Armando , Mercante Giuseppe , Spriano Giuseppe , Mancosu Pietro , Tomatis Stefano , Scorsetti Marta
Published: February 2023

Background

Prediction of survival and radiation therapy response is challenging in head and neck cancer with metastatic lymph nodes (LNs). Here we developed novel radiomics‐ and clinical‐based predictive models.

Methods

Volumes of interest of LNs were employed for radiomic features extraction. Radiomic and clinical features were investigated for their predictive value relatively to locoregional failure (LRF), progression‐free survival (PFS), and overall survival (OS) and used to build multivariate models.

Results

Hundred and six subjects were suitable for final analysis. Univariate analysis identified two radiomic features significantly predictive for LRF, and five radiomic features plus two clinical features significantly predictive for both PFS and OS. The area under the curve of receiver operating characteristic curve combining clinical and radiomic predictors for PFS and OS resulted 0.71 (95%CI: 0.60–0.83) and 0.77 (95%CI: 0.64–0.89).

Conclusions

Radiomic and clinical features resulted to be independent predictive factors, but external independent validation is mandatory to support these findings.
Resistance from the margin: An autoethnographic account of academic ableism
Authors: Kwon Chang‐kyu
Published: February 2023

Ableism—which refers to a socially‐sanctioned preference for normative bodies and minds, and which presumes one's abilities—is prevalent in any social system, including academia. However, despite an evolving disciplinary identity that seeks to improve work systems by addressing critical social issues, human resource development (HRD) as a field has done little to understand or advocate for the experiences of academics with disabilities. To challenge directly prevailing ableist assumptions and practices in academia, the present autoethnographic study was undertaken to reflect upon and detail my own experience of becoming an academic with a disability, specifically in the field of HRD. The story presented in this article presents evidence of unique challenges and opportunities facing an academic with a disability and seeks to stimulate meaningful dialogue around how to create a welcoming and inclusive academic culture for all. This article also advances autoethnography as a viable research methodology that allows for the authentic voices of members from marginalized communities and mobilizes change.
Multiple timescales of streambed flux variability in two perennial mountain‐front streams
Authors: Cognac Kristen E. , Ronayne Michael J.
Published: February 2023

Streambed fluxes are highly variable through time and space, having a range implications for stream‐aquifer processes. This study investigated streambed fluxes over a 3‐year study period to characterize short‐ and long‐term variations and related implications for seepage recharge and hyporheic exchange. Time series of streambed fluxes were estimated through Darcy‐based methods using water level and temperature inputs from shallow (<1.5 m) nested streambed piezometers installed in two mountain‐front streams in Colorado, USA. Three predominant temporal scales of variability were characterized: sub‐daily (<1 day), daily (>1 day; <1 year), and interannual (>1 year). Temporal variability was quantified using the median absolute deviation (MAD), a statistical measure that is resistant to extreme values associated with short‐duration events. Sub‐daily variability (MADS‐D) was related to ET, temperature‐induced changes in hydraulic conductivity, and variable stream stage, and was quantified using the MAD of detrended fluxes (daily mean subtracted). Daily variability (MADD), calculated as the MAD of daily median fluxes for a given year, exceeded sub‐daily variability, and was influenced by strong seasonality at some sites. For individual sites and water years, the ratio of MADS‐D to MADD ranged from 0.03 to 0.70, with an average of 0.25. Annual median fluxes at each site varied across years, but typically remained consistent in order of magnitude and direction. Results reveal a strong linear correlation between the daily variability and the median annual flux at individual sites. Within a year, summer months characterized by stronger losing conditions showed greater overall variability. 1D numerical heat and flow modelling was performed to calibrate hydraulic parameters and to investigate temperature‐related controls for sub‐daily variations. We discuss implications of documented temporal variability for analyses of hyporheic exchange and groundwater recharge. Results provide a basis for quantifying temporal variations in streambed fluxes and highlight the extent to which fluxes vary over multiple timescales.
Reproductive outcomes after pre‐implantation genetic testing in heterozygous Robertsonian translocation carriers: A retrospective cohort study of 144 cycles
Authors: Jia Miaomiao , Xue Xia
Published: February 2023

Synopsis

The purpose of this study was to evaluate meiotic segregation patterns and reproductive outcomes of pre‐implantation genetic testing (PGT) treatment in different types of RobT carriers.