bluuebunny/crossref_metadata_2025 huggingface dataset:
Venetoclax-induced vitiligo in a patient with chronic lymphocytic leukemia
Authors: Abdeen Muath , Vusqa Urwat Til , Asawa Palash , Felton Kiley , Rinchuse Derek , Khan Cyrus , Samhouri Yazan , Lister John
Published: October 2022

Venetoclax, a highly selective Bcl-2 inhibitor, is an orally bioavailable drug that has been approved as first-line therapy for chronic lymphocytic leukemia (CLL) in combination with obinutuzumab, as well as monotherapy in the setting of relapsed CLL. Although some of its life-threatening side effects are well known, including tumor lysis syndrome and cytopenias, others less known side effects include skin reactions. Skin rash is commonly reported in literature, which is often mild and not life-threatening. In this case report, the authors describe what is potentially the second case of venetoclax-induced vitiligo reported in literature. A 77-year-old man with CLL Rai stage II with cytogenetics showed 11 q23 deletion in 14% of cells, and 14q32 partial deletion in 9% of cells developed vitiligo in his extremities 2 years into treatment. A decision was made to continue venetoclax with close monitoring as the side effect was mild and not debilitating. The patient continued to do well. Although vitiligo is not associated with increased mortality risk, its development is associated with increased psychological stress. The mechanism by which vitiligo develops remains unclear. There may be an association between drug-induced vitiligo and improved cancer prognosis; however, larger studies need to be carried out to prove this hypothesis.
Accelerated Partial Breast Irradiation
Authors: Shah Chirag , Leonardi Maria C.
Published: October 2022

Partial breast irradiation (PBI) has been demonstrated to have comparable outcomes to whole breast irradiation based on multiple randomized trials with long-term follow-up. However, despite the strength of the data available, PBI remains underutilized despite being an appropriate option for many women diagnosed with early-stage breast cancer. This is significant, as PBI offers the potential to reduce toxicities and shorten treatment duration without impacting outcomes; in addition, for low-risk patients, PBI alone is being investigated as an alternative to endocrine therapy alone. Modern PBI can be delivered with multiple techniques, and advances in treatment planning have allowed for improved therapeutic ratios compared with earlier techniques; one such approach is utilizing stereotactic body radiation therapy approaches allowing for smaller target margins and therefore lower breast doses. Moving forward, studies are ongoing evaluating the use of radiation alone including PBI as compared with endocrine therapy alone, with prospective studies evaluating stereotactic body radiation therapy.
Epithelioid and Clear Cell Solitary Fibrous Tumors
Authors: Suster David I. , Mackinnon Alexander C. , Mejbel Haider A. , Gross John M. , Suster Saul
Published: October 2022

Solitary fibrous tumors (SFTs) are ubiquitous soft tissue neoplasms known for their protean histology and potentially aggressive behavior. Although most cases are composed of a monotonous proliferation of spindle cells, some tumors show unusual cytologic features. We have studied 13 SFTs that were characterized by a predominant population of round epithelioid cells with abundant eosinophilic cytoplasm and clear cell changes. The tumors occurred in 8 women and 5 men, aged 36 to 80 years (mean=63 y), and were located within the orbit (3), lower extremity (3), retroperitoneum (2), abdominal cavity (2), and superficial soft tissues of the neck, pelvis, and pubis (1 each). The tumors measured from 3.5 to 24.5 cm. Using a risk assessment system, 6 cases were stratified as low-risk tumors; 3 of these showed no evidence of recurrence or metastases from 6 to 18 years, and 1 tumor in the orbit recurred and led to the patient’s demise. Five cases were of intermediate risk; clinical follow-up showed no evidence of recurrence or metastases from 3 to 4 years in 3 patients, and 1 patient suffered a recurrence 4 years after diagnosis. Two cases were high risk; 1 patient died after 1 year and the second patient experienced local recurrence at 4 years. Immunohistochemical studies showed nuclear positivity for STAT6 in 10 cases. CD34 immunohistochemistry was positive in 11 cases. A NAB2::STAT6 rearrangement was present in all cases. Epithelioid and clear cell SFT should be considered in the differential diagnosis of soft tissue neoplasms with epithelioid and clear cell morphology.
Reduction of Central-line–Associated Bloodstream Infections in a Tertiary Neonatal Intensive Care Unit through Simulation Education
Authors: Hightower Hannah B. , Young John Andrew , Thomas Jennifer , Smith Jill Jones , Hobby-Noland Delphene , Palombo Georgina , McCaskey Marjorie , Benton Beth , Hutto Cecelia , Coghill Carl , McCullough Becky , Hayes Leslie , Martin Colin , Chewning Joseph H.
Published: October 2022

Introduction:

Critically ill neonates and those with complex medical conditions frequently require the use of central venous lines. Unfortunately, central line-associated bloodstream infections (CLABSIs) result in significant morbidity and mortality, and the cost and increased length of stay burden the healthcare system. Previous studies have demonstrated that standardized care bundles can decrease CLABSI rates, but achieving sustained improvement has proven difficult.

Methods:

All patients admitted to the Neonatal Intensive Care Unit between 2014 and 2020 who had a CVL were included in this study. First, we recorded all CLABSI events and total CVL days according to defined criteria. Then, in late 2016, we instituted simulation-based nursing training for CVL care.

Results:

Job Instruction Sheets were initially introduced to Neonatal Intensive Care Unit nursing staff simultaneously with one-on-one teaching sessions between instructors and bedside nurses. Intermittent performance audits and re-education for identified deficiencies did not improve the CLABSI rate per 1000 line days. After instituting simulation-based CVL training in 2016, there was a decreased rate of CLABSI events per 1000 line days sustained over time (x = 0.692).

Conclusions:

Standardized care bundles and Hospital-acquired Condition interactor audits were insufficient to reduce the CLABSI rate. However, combining care bundles and education with simulation-based training significantly decreased CLABSI rates. One-on-one intensive training and continued ongoing monitoring were critical to producing a sustained reduction. This experience demonstrates that supervised, interactive education combined with simulation can significantly impact patient outcomes.
Birth Country Influences the Choice of Antiretroviral Therapy in HIV-Infected Individuals: Experience From a French HIV Centre
Authors: Palich Romain , Agher Rachid , Wetshikoy Dimoke J. , Cuzin Lise , Seang Sophie , Soulie Cathia , Tubiana Roland , Valantin Marc-Antoine , Schneider Luminita , Pourcher Valérie , Marcelin Anne-Geneviève , Assoumou Lambert , Katlama Christine
Published: October 2022

Objectives:

To assess whether antiretroviral therapy (ART) prescriptions differ between naive and virally suppressed HIV patients born in France (PBFs) and in Sub-Saharan Africa (PBSSAs).

Setting:

Observational single-center study.

Methods:

We included all PBFs and PBSSAs who entered into care at Pitié-Salpêtrière Hospital, Paris, France, from 01/01/2000 to 31/12/2018, with plasma HIV-RNA>200 copies/mL. We first compared the initial ART in naive PBFs and PBSSAs. Second, we compared the last-prescribed ART (including drug-reduced ART: daily 2-drug regimens, daily 1-drug regimens and intermittent 3-drug regimens) in virally suppressed PBFs and PBSSAs, by focusing on patients in care in 2018 with HIV-RNA <50 copies for at least 24 months. A univariable and multivariable logistic regression model was used to assess the impact of geographical origin on ART prescriptions.

Results:

A total of 1944 naive patients were included (915 PBSSAs and 1029 PBFs). PBSSAs were more frequently women, hepatitis B coinfected, with a lower pretherapeutic CD4 T-cell count, and most had tuberculosis at HIV diagnosis. After adjustment for confounders, PBSSAs were more likely to receive a first-line protease inhibitor-based regimen (OR 1.61, 95% CI: 1.31 to 1.98), and less likely to receive an integrase inhibitor-based regimen (OR 0.61, 95% CI: 0.42 to 0.88). Of the 968 virally suppressed patients (431 PBSSAs and 537 PBFs), PBSSAs were less likely to receive drug-reduced ART, including 2-drug regimens and intermittent three-drug regimens (OR 0.48, 95% CI: 0.36 to 0.65).

Conclusions:

Differences in ART prescriptions between PBSSAs and PBFs were not only explained by different clinical and virologic situations. Personal motivations of doctors in choosing ART according to country of birth need to be explored.
FDG PET/CT in Immune-Related Arthritis in a Patient Treated With Nivolumab
Authors: Bayat Mohadeseh , Doroudinia Abtin , Karam Mehrdad Bakhshayesh , Mehrian Payam
Published: October 2022

Immune checkpoint inhibitors are a new and different treatment option in many of solid tumors, but with many recognized immune-related adverse side effects. In this interesting image, we are presenting a 56-year-old woman with primary malignant melanoma who underwent nivolumab therapy for 5 months, and a posttreatment whole-body FDG PET/CT scan for treatment response evaluation demonstrated increased metabolic activity in the entire major joints of the upper and lower extremities. This was a new finding compared with previous FDG PET/CT scan and was interpreted as an immune-related arthritis complication.
Transient Bilateral Central Scotoma on Awakening: A Distinct Phenomenon
Authors: Sanchez Moreno Francisco R. , Mansukhani Sasha A. , Bhatti M. Tariq , Chen John J.
Published: October 2022

Background:

Transient vision loss can be an alarming symptom owing to potentially serious etiologies such as thromboembolism or giant cell arteritis. Transient monocular vision loss (TVML) on awakening has been recently described as a benign phenomenon (Bouffard et al, 2017). Our objective was to describe the unique phenomenon of transient binocular vision loss (TBVL) on awakening.

Methods:

Retrospective observational case series of 5 patients who experienced TBVL on awakening seen in the neuro-ophthalmology clinic at the Mayo Clinic between 2016 and 2020. Patients who described generalized blurred vision and those with monocular transient vision loss were excluded.

Results:

The median age was 81.4 years (range, 68–92 years), and all were male. Every patient described a stereotyped transient bilateral central scotoma on awakening with slightly irregular borders and mild asymmetry between the 2 eyes lasting between 15 and 90 minutes. Frequency ranged from 3 to 7 times per week, and there was a median of 319 episodes (range, 126–728 episodes) before evaluation in the neuro-ophthalmology clinic. All patients had normal optic nerves, and no plaques were noted in the retinal vessels. All 5 had macular drusen, which were predominantly extrafoveal and mild. Two patients underwent electrophysiology testing, which were both normal on full-field electroretinogram (ERG), but there was blunted central wave forms on multifocal ERG. Two patients underwent dark adaptation testing, which showed both prolong and diminished dark adaptation. Neuroimaging and thromboembolic workup were unrevealing.

Conclusions:

TBVL is a distinct phenomenon from TMVL on awakening, which has a different demographic and symptomology. The etiology is unclear but seems to be a focal macular process in conjunction with an autoregulatory failure resulting in a supply–demand mismatch during low-light conditions.
Transparent and stretchable metal nanowire composite recording microelectrode arrays
Authors: Chen Zhiyuan , Nguyen Khanh , Kowalik Grant , Shi Xinyu , Tian Jinbi , Doshi Mitansh , Alber Bridget R. , Ning Xin , Kay Matthew W. , Lu Luyao
Published: October 2022

Transparent microelectrodes have received much attention from the biomedical community due to their unique advantages in concurrent crosstalk-free electrical and optical interrogation of cell/tissue activity. Despite recent progress in constructing transparent microelectrodes, a major challenge is to simultaneously achieve desirable mechanical stretchability, optical transparency, electrochemical performance, and chemical stability for high-fidelity, conformal, and stable interfacing with soft tissue/organ systems. To address this challenge, we have designed microelectrode arrays (MEAs) with gold coated silver nanowires (Au-Ag NWs) by combining technical advances in materials, fabrication, and mechanics. The Au coating improves both the chemical stability and electrochemical impedance of the Au-Ag NWs microelectrodes with only slight changes in optical properties. The MEAs exhibit a high optical transparency >80% at 550 nm, a low normalized 1 kHz electrochemical impedance of 1.2-7.5 Ω cm2, stable chemical and electromechanical performance after exposure to oxygen plasma for 5 minutes and cyclic stretching for 600 cycles at 20% strain, superior to other transparent microelectrode alternatives. The MEAs easily conform to curvilinear heart surfaces for co-localized electrophysiological and optical mapping of cardiac function. This work demonstrates that stretchable transparent metal nanowire MEAs are promising candidates for diverse biomedical science and engineering applications, particularly under mechanically dynamic conditions.
Phylogeography ofGeothelphusafreshwater crabs: unexpected dual dispersal routes via land and sea
Authors: Masaki Takenaka , Koki Yano , Koji Tojo
Published: October 2022

Aim

Dispersal is an important factor that determines the potential for colonization to pioneer sites. Most decapods employ seaward migration for reproduction with a planktonic larval phase. However, true freshwater crabs spend their entire life cycle in freshwater. Therefore, it is expected that genetic regionality can be easily detected. In this study, we focused on the genetic structures of true freshwater crabs,Geothelphusacrabs. Herein, we reveal the evolutionary history and dispersal patterns of freshwater crustaceans, for which there is limited knowledge to date.

Location

Japanese Islands

Taxon

Geothelphusa dehaani(Decapoda, Potamidae)

Methods

We collected and genetically analyzed 283 specimens at 138 localities from freshwater habitats across the Japanese Islands. Phylogenetic analyses were conducted on 1,796 bp of the combined dataset (mtDNA COI, 16S, and nDNA ITS1, histone H3) and 569 bp of the mtDNA COI dataset. The demographic history ofG. dehaaniwas simulated using Approximate Bayesian Computation analysis. A salt tolerance experiment was conducted to confirm the survival rate in seawater.

Results

The resulting of phylogenetic relationships detected 10 clades that were highly likely to be monophyletic. These 10 clades genetically exhibited an explicit pattern of geographical differentiation. Also, we confirmed the salt tolerance ability of these Japanese freshwater crabs.

Main conclusions

The highlights of this study were the discovery of several cryptic species/lineages or undescribed species, and the completely different heterogeneous dual dispersal pathways detected within a single species; i.e., both land and ocean routes. As a result of phylogenetic analysis, it was concluded that Japanese crabs are basically genetically divided by straits. However, strong evidence for dispersion via ocean currents was also detected (i.e., a “sweepstake”), and it was also determined thatG. dehaanicould survive in seawater. This is the first observation of such a unique mode of expansion of a species’ distribution area.
Environment-mediated vertical transmission fostered uncoupled phylogenetic relationships between longicorn beetles and their symbionts
Authors: Sasakura Yasunori , Yuzawa Nobuhisa , Yamasako Junsuke , Mori Kazuki , Horie Takeo , Nonaka Masaru
Published: October 2022

The Coleoptera Cerambycidae (longicorn beetles) use wood under different states (living healthy, freshly snapped, completely rot, etc.) in a species-specific manner for their larval diet. Larvae of some Cerambycidae groups have mycetomes, accessory organs associated with the midgut that harbor fungal symbiont cells. The symbionts are thought to improve nutrient conditions; however, this has yet to be shown experimentally. To deduce the evolutionary history of this symbiosis, we investigated the characteristics of the mycetomes in the larvae of longicorn beetles collected in Japan. Lepturinae, Necydalinae, and Spondylidinae are the only groups that possess mycetomes, and these three groups’ mycetomes and corresponding fungal cells exhibit different characteristics between the groups. However, the phylogenetic relationship of symbiont yeasts does not coincide with that of the corresponding longicorn beetle species, suggesting they have not co-speciated. The imperfect vertical transmission of symbiont yeasts from female to offspring is a mechanism that could accommodate the host-symbiont phylogenetic incongruence. Some Lepturinae species secondarily lost mycetomes. The loss is associated with their diet choice, suggesting that different conditions between feeding habits could have allowed species to discard this organ. We found that symbiont fungi encapsulated in the mycetomes are dispensable for larval growth if sufficient nutrients are given, suggesting that the role of symbiotic fungi could be compensated by the food larvae take.Aegosoma sinicumis a longicorn beetle classified to the subfamily Prioninae, which does not possess mycetomes. However, this species contains a restricted selection of yeast species in the larval gut, suggesting that the symbiosis between longicorn beetles and yeasts emerged before acquiring the mycetomes.
Thalamocortical networks involved in Pusher Syndrome
Authors: Rosenzopf Hannah , Klingbeil Julian , Wawrzyniak Max , Röhrig Lisa , Sperber Christoph , Saur Dorothee , Karnath Hans-Otto
Published: October 2022

Indirect quantification of functional and structural disconnection increases the knowledge derived from focal brain lesions by inferring subsequent brain network damage from the respective lesion. We applied both measures to a sample of 124 stroke patients to investigate brain disconnection in pusher syndrome – a disorder characterized by a disturbed perception of one’s own upright body posture. Our results suggest a hub-like function of the posterior and lateral portions of the thalamus in the perception of one’s own postural upright and identified dysfunction in a thalamo-cortical network as one likely cause of pusher syndrome. Lesion network-symptom-mapping investigating functional disconnection indicated cortical diaschisis in cerebellar, frontal, parietal, occipital, and temporal areas in patients with thalamic lesions suffering from pusher syndrome, but there was no evidence for functional diaschisis in cortical stroke and no evidence for the convergence of thalamic and cortical lesions onto a common functional network. Structural disconnectivity mapping identified several thalamo-cortical disconnections. Many of the thalamic and cortical regions disconnected by lesions that lead to pusher behavior correspond to previously reported lesion sites associated with pusher syndrome. Thus, while the presence of both, isolated thalamic and cortical lesions in context with pusher behavior has been reported previously and led to the conclusion that the correct estimation of one’s own postural upright might depend on a thalamo-cortical network, our analyses offer the first evidence for a direct thalamo-cortical (or cortico-thalamic) interconnection and, more importantly, shed light on the location of the respective thalamo-cortical disconnections.
MIND Networks: Robust Estimation of Structural Similarity from Brain MRI
Authors: Sebenius Isaac , Seidlitz Jakob , Warrier Varun , Bethlehem Richard A I , Alexander-Bloch Aaron , Mallard Travis T , Garcia Rafael Romero , Bullmore Edward T , Morgan Sarah E
Published: October 2022

Structural similarity networks are a central focus of magnetic resonance imaging (MRI) research into human brain connectomes in health and disease. We present Morphometric INverse Divergence (MIND), a robust method to estimate within-subject structural similarity between cortical areas based on the Kullback-Leibler divergence between the multivariate distributions of their structural features. Compared to the prior approach of morphometric similarity networks (MSNs) on N>10,000 data from the ABCD cohort, MIND networks were more consistent with known cortical symmetry, cytoarchitecture, and (in N=19 macaques) gold-standard tract-tracing connectivity, and were more invariant to cortical parcellation. Importantly, MIND networks were remarkably coupled with cortical gene co-expression, providing fresh evidence for the unified architecture of brain structure and transcription. Using kinship (N=1282) and genetic data (N=4085), we characterized the heritability of MIND phenotypes, identifying stronger genetic influence on the relationship between structurally divergent regions compared to structurally similar regions. Overall, MIND presents a biologically-validated lens for analyzing the structural organization of the cortex using readily-available MRI measurements.
ERK3/MAPK6 dictates Cdc42/Rac1 activity and ARP2/3-dependent actin polymerization
Authors: Bogucka-Janczi Katarzyna , Harms Gregory , May-Coissieux Mary , Bentires-Alj Mohamad , Thiede Bernd , Rajalingam Krishnaraj
Published: October 2022

The actin cytoskeleton is tightly controlled by RhoGTPases, actin binding proteins and nucleation-promoting factors to perform fundamental cellular functions. Here, we show that ERK3, an atypical MAPK, directly acts as a guanine nucleotide exchange factor for Cdc42 and phosphorylates the ARP3 subunit of the ARP2/3 complex at S418 to promote filopodia formation and actin polymerization, respectively. Consistently, depletion of ERK3 prevented both basal and EGF-dependent Rac1 and Cdc42 activation, maintenance of F-actin content, filopodia formation and epithelial cell migration. Further, ERK3 protein binds directly to the purified ARP2/3 complex and augments polymerization of actinin vitro. ERK3 kinase activity is required for the formation of actin-rich protrusions in mammalian cells. These findings unveil a fundamentally unique pathway employed by cells to control actin-dependent cellular functions.
Development of Multi-Bundle Virtual Ligaments to Simulate Knee Mechanics after Total Knee Arthroplasty
Authors: Vakili Samira , Lanting Brent , Getgood Alan , Willing Ryan
Published: October 2022

Preclinical evaluation of total knee arthroplasty (TKA) components is essential to understanding their mechanical behavior and developing strategies for improving joint stability. While preclinical testing of TKA components has been useful in quantifying their effectiveness, such testing can be criticized for lacking clinical relevance, as the important contributions of surrounding soft tissues are either neglected or greatly simplified. The purpose of our study was to develop and determine if subject-specific virtual ligaments reproduce the same kinematics as native ligaments surrounding TKA joints. Five TKA knees were mounted to a motion simulator. Each was subjected to tests of anterior-posterior (AP), internal-external (IE), and varus-valgus (VV) laxity. The forces transmitted through major ligaments were measured using a sequential resection technique. By tuning the measured ligament forces and elongations to a generic non-linear elastic ligament model, virtual ligaments were designed and used to simulate the soft tissue envelope around isolated TKA components. The average root mean square error (RMSE) between the laxity results of TKA joints with native versus virtual ligaments was 2.9 mm during AP translation, 6.5° during IE rotations, and 2.0° during VV rotations, and there was no statistically significant difference between the results of both methods. Interclass correlation coefficients (ICCs) indicated a good level of reliability for AP and IE laxity (0.85 and 0.84). To conclude, a virtual ligament envelope around TKA joints can mimic natural knee behavior and is an effective method for the preclinical testing of TKA components.
Widespread enhancer co-activity identified by multimodal single cell analysis
Authors: Ziyani Chaymae , Delaneau Olivier , Ribeiro Diogo M.
Published: October 2022

Non-coding regulatory elements such as enhancers are key in controlling the cell type-specificity and spatio-temporal expression of genes. To drive stable and precise gene transcription that is robust to genetic variation and environmental stress, genes are often targeted by multiple enhancers with redundant action. However, it is unknown whether enhancers targeting the same gene display simultaneous activity or whether some enhancer combinations are more often co-active than others. Here, we take advantage of the recent developments in single cell technology that permit assessing chromatin status (scATAC-seq) and gene expression (scRNA-seq) in the same single cells to link gene expression to the activity of multiple enhancers. Measuring activity patterns across 24,844 human lymphoblastoid single cells, we found that the majority of enhancers associated with the same gene display significant correlation in their chromatin profiles. For 6944 expressed genes associated with enhancers, we identified 89,885 significant enhancer-enhancer associations between nearby enhancers. We found that associated enhancers share similar transcription factor binding profiles and that gene essentiality is linked with higher enhancer co-activity. Our extensive enhancer co-activity maps can be used to pinpoint combinations of enhancers relevant in gene expression regulation and allow us to better predict the effect of genetic variation falling in non-coding regions.
Export of discarded splicing intermediates requires mRNA export factors and the nuclear basket
Authors: Zeng Yi , Staley Jonathan P.
Published: October 2022

To promote fidelity in nuclear pre-mRNA splicing, the spliceosome rejects and discards suboptimal splicing substrates after they have engaged the spliceosome. Although nuclear quality control mechanisms have been proposed to retain immature mRNPs, evidence indicates that discarded splicing substrates, including lariat intermediates, do export to the cytoplasm, as indicated by their translation and degradation by cytoplasmic nucleases. However, the mechanism for exporting these species has remained unknown. By single molecule (sm) RNA FISH in budding yeast, we have directly observed the nuclear export of lariat intermediates. Further, by crosslinking, export reporter assays, and smRNA FISH, we have demonstrated that the export of lariat intermediates requires the general mRNA export receptor Mex67p and three of its mRNA export adapter proteins, Nab2p, Yra1p, and Nlp3, establishing that mRNAs and lariat intermediates share the same export machinery. Unexpectedly, the export of lariat intermediates, but not mRNA, requires an interaction between Nab2p and Mlp1p, a nuclear basket component implicated in retaining immature mRNPs, including unspliced pre-mRNA, in the nucleus of budding yeast. Finally, the export of lariat intermediates, like mRNA, relies on the E3 ubiquitin ligase Tom1p and its target sites in Yra1p. Overall, our data indicate that the nuclear basket can promote, rather than antagonize, the export of an immature mRNP. Further, our data imply that the export of discarded lariat intermediates requires both Mlp1p-dependent docking onto the nuclear basket and subsequent Tom1p-mediated undocking, a mechanism our data suggests functions in the export of mRNA also but in a manner obscured by redundant pathways.
Chemical inhibition of PIN auxin transporters by the anti-inflammatory drug Naproxen
Authors: Xia Jing , Kong Mengjuan , Yang Zhisen , Sun Lianghanxiao , Peng Yakun , Wei Hong , Ying Wei , Gao Yongxiang , Friml Jiří , Liu Xin , Sun Linfeng , Tan Shutang
Published: October 2022

The phytohormone auxin plays central roles in many growth and developmental processes in plants. Development of chemical tools targeting the auxin pathway is useful for both plant biology and agriculture. Here we uncover that Naproxen, a synthetic compound with anti-inflammatory activity in humans, acts as an auxin transport inhibitor targeting PIN transporters in plants. Physiological experiments indicate that exogenous Naproxen treatment affects pleiotropic auxin-regulated developmental processes. Further cellular and biochemical evidence supports that Naproxen suppresses auxin transport, specifically PIN-mediated auxin efflux. Moreover, biochemical and structural analysis confirms that Naproxen binds directly to PIN1 protein, via the same binding cavity as the IAA substrate. Thus, by combining cellular, biochemical, and structural approaches, this study well establishes that Naproxen is a PIN inhibitor and elucidates the underlying mechanisms. Further use of the compound may advance our understanding on the molecular mechanisms of PIN-mediated auxin transport, and expand our toolkit in auxin biology and agriculture.
A stem cell zoo uncovers intracellular scaling of developmental tempo across mammals
Authors: Lázaro Jorge , Costanzo Maria , Sanaki-Matsumiya Marina , Girardot Charles , Hayashi Masafumi , Hayashi Katsuhiko , Diecke Sebastian , Hildebrandt Thomas B. , Lazzari Giovanna , Wu Jun , Petkov Stoyan , Behr Rüdiger , Trivedi Vikas , Matsuda Mitsuhiro , Ebisuya Miki
Published: October 2022

Differential speeds in biochemical reactions have been proposed to be responsible for the differences in developmental tempo between mice and humans. However, the underlying mechanism controlling the species-specific kinetics remains to be determined. Usingin vitrodifferentiation of pluripotent stem cells, we recapitulated the segmentation clocks of diverse mammalian species varying in body weight and taxa: marmoset, rabbit, cattle and rhinoceros. Together with the mouse and human, the segmentation clock periods of the six species did not scale with the animal body weight, but were rather grouped according to phylogeny. The biochemical kinetics of the core clock gene HES7 displayed clear scaling with the species-specific segmentation clock period. However, the cellular metabolic rates did not show an evident correlation. Instead, genes involving biochemical reactions showed an expression pattern that scales with the segmentation clock period. Altogether, our stem cell zoo uncovered general scaling laws governing species-specific developmental tempo.*
Metabolite profiling and cytotoxic activity of Andean potatoes: polyamines and glycoalkaloids as potential anticancer agents in human neuroblastoma cellsin vitro
Authors: Lanteri María Luciana , Silveyra María Ximena , Morán Mónica Mariela , Boutet Stéphanie , Solis-Gozar Deyvis-Dante , Perreau François , Andreu Adriana Balbina
Published: October 2022

Andean potatoes (Solanum tuberosumL. ssp.andigena) are a good source of dietary antioxidant polyphenols. We have previously demonstrated that polyphenol extracts from Andean potato tubers exerted a dose-dependent cytotoxic effect in human neuroblastoma SH-SY5Y cells, being skin extracts more potent than flesh ones. In order to gain insight into the bioactivities of potato phenolics, we investigated the composition and thein vitrocytotoxic activity of total extracts and fractions of skin and flesh tubers of three Andean potato cultivars (Santa María, Waicha, and Moradita). Potato total extracts were subjected to liquid-liquid fractionation using ethyl acetate solvent in organic and aqueous fractions. We analyzed both fractions by HPLC-DAD, HPLC-ESI-MS/MS, and HPLC-HRMS. Results corroborated the expected composition of each fraction. Organic fractions were rich in hydroxycinnamic acids (principally chlorogenic acid isomers), whereas aqueous fractions contained mainly polyamines conjugated with phenolic acids, glycoalkaloids, and flavonoids. Organic fractions were not cytotoxic against SH-SY5Y cells, and indeed, some increased cellular metabolism compared to controls. Aqueous fractions were cytotoxic and even more potent than their respective total extracts. Treatment with a combination of both fractions showed a similar cytotoxic response to the corresponding extract. According to correlation studies, it is tempting to speculate that polyamines and glycoalkaloids are crucial in inducing cell death. Our findings indicate that the activity of Andean potato extracts is a combination of various compounds and contribute to the revalorization of potato as a functional food.
Global scientific research in Microbial Induced Calcite Precipitation: A bibliometric network analysis
Authors: Jarwar Mazhar Ali , Dumontet Stefano , Nastro Rosa Anna , Sanz-Montero M. Esther , Pasquale Vincenzo
Published: October 2022

Microbial Induced Calcite Precipitation (MICP) offers a host of interesting features, both from theoretical and practical standpoints. This process was firstly investigated as a geo-biological mechanism involved in carbonate mineral formation both in rocks and soil. The interest towards its practical use significantly increased in the recent years, as MICP was used in different fields, such as oil recovery, improvement of soil geotechnical characteristics and concreate healing. To the best of our knowledge, this paper is the first attempt to carry out a bibliometric descriptive study of publications on MICP. We analyzed data from the Web of Science Core Collection (WoSCC), which provides comprehensive information for bibliometric analysis, including the Science Citation Index-Expanded (SCI-E) and the Social Sciences Citation Index (SSCI). The bibliometric analysis was carried out on 1580 publications, from 2000 to August 2022, and included publication output, author, institution, country, collaborations between authors, institutes and countries, and citation frequency. We created visualization maps including research collaborations by using the VOSviewer program. MICP, carbonate precipitation, cementation, and soil improvement in terms of geotechnical properties are high-frequency used keywords. Although in the year 2000 only two papers were published on MICP, the number of publications increased rapidly since 2014. In 2021, 333 papers were published. China leads as the most productive country, followed by USA and Australia. According to our results, the number of research papers dramatically increased in the last 5 years. MICP with concrete healing/cementation, soil geotechnical improvement, and the low environmental impact of such a technique are becoming very popular topics among researchers. With the ageing of concrete buildings, as well as with the worsening of environmental pollution and soil alterations, the research about MICP will play an ever increasing and crucial role in civil engineering and geotechnical issues and in soil science. Nevertheless, our study pointed out a sort of concentration of the MICP studies in few countries. Russia and Brazil, for instance, seems to poorly contribute to MICP researches. A larger cooperation among countries, together with the extension of the research network on this topic, would considerably foster the progress in MICP studies, from both practical and speculative standpoints.
Dicentric chromosome breakage inDrosophila melanogasteris influenced by pericentric heterochromatin and reveals a novel class of fragile site
Authors: Hill Hunter , Bonser Danielle , Golic Kent G.
Published: October 2022

Chromosome breakage plays an important role in the evolution of karyotypes, and can produce deleterious effects within a single individual, such as aneuploidy or cancer. Forces that influence how and where chromosomes break are not well understood. In humans, breakage tends to occur in conserved hotspots called common fragile sites (CFS), especially during replication stress. By following the fate of dicentric chromosomes inDrosophila melanogasterwe find that breakage under tension also tends to occur in specific hotspots. Our experimental approach was to induce sister chromatid exchange in a ring chromosome to generate a dicentric chromosome with a double chromatid bridge. In the following cell division, the dicentric bridges may break. We analyzed the breakage patterns of three different ring-Xchromosomes. These chromosomes differ by the amount and quality of heterochromatin they carry as well as their genealogical history. For all three chromosomes, breakage occurs preferentially in several hotspots. Surprisingly, we found that the hotspot locations are not conserved between the three chromosomes: each displays a unique array of breakage hotspots. The lack of hotspot conservation, along with a lack of response to aphidicolin, suggests that these breakage sites are not entirely analogous to CFS and may reveal new mechanisms of chromosome fragility.. Additionally, the frequency of dicentric breakage and the durability of their spindle attachment varies significantly between the three chromosomes and is correlated with the origin of the centromere and the amount of pericentric heterochromatin they carry. We suggest that different centromere strengths could account for this.
Chromosome-level genome assembly ofEuphorbia peplus, a model system for plant latex, reveals that relative lack of Ty3 transposons contributed to its small genome size
Authors: Johnson Arielle R. , Yue Yuanzheng , Carey Sarah B. , Park Se Jin , Kruse Lars H. , Bao Ashley , Harkess Alex , Pasha Asher , Provart Nicholas J. , Moghe Gaurav D. , Frank Margaret H.
Published: October 2022

Euphorbia peplus(petty spurge) is a small, fast-growing plant that is native to Eurasia and has become a naturalized weed in North America and Australia.E. peplusis not only medicinally valuable, serving as a source for the skin cancer drug ingenol mebutate, but also has great potential as a model for latex production owing to its small size, ease of manipulation in the laboratory, and rapid reproductive cycle. To help establishE. peplusas a new model, we generated a 267.2 Mb HiC-anchored PacBio HiFi nuclear genome assembly with an embryophyta BUSCO score of 98.5%, a genome annotation based on RNA-seq data from six tissues, and publicly accessible tools including a genome browser and an interactive organ-specific expression atlas. Chromosome number is highly variable acrossEuphorbiaspecies. Using a comparative analysis of our newly sequencedE. peplusgenome with other Euphorbiaceae genomes, we show that variation inEuphorbiachromosome number is likely due to fragmentation and rearrangement rather than aneuploidy. Moreover, we found that theE. peplusgenome is relatively compact compared to related members of the genus in part due to restricted expansion of the Ty3 transposon family. Finally, we identify a large gene cluster that contains many previously identified enzymes in the putative ingenol mebutate biosynthesis pathway, along with additional gene candidates for this biosynthetic pathway. The genomic resources we have created forE. pepluswill help advance research on latex production and ingenol mebutate biosynthesis in the commercially important Euphorbiaceae family.

Significance statement

Euphorbiais one of the five largest genera in the plant kingdom. Despite an impressive phenotypic and metabolic diversity in this genus, only oneEuphorbiagenome has been sequenced so far, restricting insights intoEuphorbiabiology.Euphorbia peplushas excellent potential as a model species due to its latex production, fast growth rate and production of the anticancer drug ingenol mebutate. Here, we present a chromosome-levelE. peplusgenome assembly and publicly accessible resources to support molecular research for this unique species and the broader genus. We also provide an explanation of one reason the genome is so small, and identify more candidate genes for the anticancer drug and related compounds.
The possibility of anesthesia stimulated by a train of current pulses
Authors: Shneider Mikhail N. , Pekker Mikhail
Published: October 2022

This paper considers a simple theoretical model of blocking the passage of signals (action potentials) from sensory neurons and thereby effecting anesthesia without the use of anesthetics as a result of a sequence of unipolar current pulses generated by an external source. The proposed model allows the selection of parameters and the required frequency of the repetition of current pulses for the possible implementation of anesthesia depending on the electrical characteristics of the skin and the conductivity of the saline solution in which the myelinated nerve fibers are located.
A fast and versatile method for simultaneous HCR, immunohistochemistry and EdU labeling (SHInE)
Authors: Ćorić Aida , Stockinger Alexander W. , Schaffer Petra , Rokvić Dunja , Tessmar-Raible Kristin , Raible Florian
Published: October 2022

Access to newer, fast and cheap sequencing techniques, particularly on the single-cell level, have made transcriptomic data of tissues or single cells accessible to many researchers. As a consequence, there is increased need forin situvisualization of gene expression or encoded proteins to validate, localize or help interpret such sequencing data, as well as put them in context with cellular proliferation. A particular challenge for labeling and imaging transcripts are complex tissues that are often opaque and/or pigmented, preventing easy visual inspection. Here we introduce a versatile protocol that combinesin situhybridization chain reaction (HCR), immunohistochemistry (IHC) and proliferative cell labeling using 5-ethynyl-2’-deoxyuridine (EdU), and demonstrate its compatibility with tissue clearing. As a proof-of-concept, we show that our protocol allows for the parallel analysis of cell proliferation, gene expression and protein localization in bristleworm heads and trunks.
Distinct steady-state properties and TNF responses of epithelial long myosin light chain kinase (MLCK) splice variants
Authors: Chanez-Paredes Sandra D. , Abtahi Shabnam , Zha Juanmin , Zuo Li , He Weiqi , Turner Jerrold R.
Published: October 2022

Intestinal epithelia express two long myosin light chain kinase (MLCK) splice variants, MLCK1 and MLCK2. Unlike MLCK2, MLCK1 is concentrated at the perijunctional actomyosin ring and this localization is enhanced by tumor necrosis factor (TNF) signaling. Here we sought to identify and characterize the domain(s) that direct basal and TNF-induced MLCK1 subcellular localization. Quantitative morphometry demonstrated specific increases in MLCK1 expression and perijunctional localization in Crohn’s disease patient biopsies, relative to controls. TNF induced perijunctional recruitment of MLCK1-EGFP but did not affect localization of MLCK2-EGFP, which was predominantly associated with basal stress fibers. Recombinant N-terminal MLCK1 and MLCK2 regions accelerated actin polymerization in vitro but were not different from one another. In contrast, the affinity of N-terminal MLCK1 binding to F-actin was greater than that of MLCK2. Perijunctional MLCK1 and MLCK2 domain recruitment in intestinal epithelial cells paralleled in vitro F-actin binding. The unique MLCK1 Ig3 domain was necessary, but not sufficient, for both F-actin binding and perijunctional recruitment, but, nevertheless, displaced perijunctional MLCK1, enhanced steady-state barrier function, and limited TNF-induced MLCK1 recruitment and barrier loss. These data demonstrate selective perijunctional MLCK1 recruitment in Crohn’s disease, suggest that F-actin binding contributes to perijunctional recruitment, and show that Ig3 can act as a dominant negative effector that limits TNF-induced MLCK1 recruitment and barrier loss. These results data provide key mechanistic detail that will enable development of therapeutics that target Ig3, or its intercellular binding partners, to reverse inflammation-induced barrier loss and limit disease progression.
Declining autozygosity over time: an exploration in over 1 million individuals from three diverse cohorts
Authors: Colbert Sarah M.C. , Wendt Frank R. , Pathak Gita A. , Helmer Drew A. , Hauser Elizabeth R. , Keller Matthew C. , Polimanti Renato , Johnson Emma C.
Published: October 2022

We hypothesized that overall autozygosity is decreasing over generational time. In this report, we present data that partially support this hypothesis from three large cohorts of diverse ancestries, two from the US (All of Us and the Million Veteran Program, N=82,474 and 622,497, respectively) and one from the UK (UK Biobank, N=380,899). Our results from a mixed-effect meta-analysis demonstrate an overall trend of decreasing autozygosity over generational time (meta-analyzed slope=-0.029, se=0.009, p=6.03e-4). Using a chi-square difference test, we determined that a model including an ancestry-by-country interaction term fit the data best, indicating that ancestry differences in this trend differ by country. We found further evidence to suggest a difference between the US and UK cohorts by meta-analyzing within country, observing a significant negative estimate in the US cohorts (meta-analyzed slope=-0.058, se=0.015, p=1.50e-4) but a non-significant estimate in the UK (meta-analyzed slope=-0.001, se=0.008, p=0.945). We also found that the association between autozygosity and year of birth in the overall meta-analysis was substantially attenuated when accounting for educational attainment and income (meta-analyzed slope=-0.011, se=0.008, p=0.167), suggesting that increases in education and income may partially account for decreasing levels of autozygosity over time. To our knowledge, this is the largest demonstration of decreasing autozygosity over time in a modern sample (birth years 1904-2003), and we speculate that this trend can be attributed to increases in population size, urbanization and panmixia, with differences in demographic and sociocultural processes leading to country-specific differences in the rate of decline.