bluuebunny/crossref_metadata_2025 huggingface dataset:
RESET-PKD: a pilot trial on short-term ketogenic interventions in autosomal dominant polycystic kidney disease
Authors: Oehm Simon , Steinke Konstantin , Schmidt Johannes , Arjune Sita , Todorova Polina , Heinrich Lindemann Christoph , Wöstmann Fabian , Meyer Franziska , Siedek Florian , Weimbs Thomas , Müller Roman-Ulrich , Grundmann Franziska
Published: November 2022

Background

Ketogenic dietary interventions (KDI) have been shown to be effective in animal models of polycystic kidney disease (PKD), but data from clinical trials are lacking.

Methods

Ten autosomal dominant PKD (ADPKD) patients with rapid disease progression were enrolled at visit V1 and initially maintained a carbohydrate-rich diet. At V2, patients entered one of the two KDI arms: a 3-day water fast (WF) or a 14-day ketogenic diet (KD). At V3, they resumed their normal diet for 3–6 weeks until V4. At each visit, magnetic resonance imaging kidney and liver volumetry was performed. Ketone bodies were evaluated to assess metabolic efficacy and questionnaires were used to determine feasibility.

Results

All participants [KD n = 5, WF n = 5; age 39.8 ± 11.6 years; estimated glomerular filtration rate 82 ± 23.5 mL/min/1.73 m2; total kidney volume (TKV) 2224 ± 1156 mL] were classified as Mayo Class 1C–1E. Acetone levels in breath and beta-hydroxybutyrate (BHB) blood levels increased in both study arms (V1 to V2 average acetone: 2.7 ± 1.2 p.p.m., V2 to V3: 22.8 ± 11.9 p.p.m., P = .0006; V1 to V2 average BHB: 0.22 ± 0.08 mmol/L, V2 to V3: 1.88 ± 0.93 mmol/L, P = .0008). Nine of 10 patients reached a ketogenic state and 9/10 evaluated KDIs as feasible. TKV did not change during this trial. However, we found a significant impact on total liver volume (ΔTLV V2 to V3: −7.7%, P = .01), mediated by changes in its non-cystic fraction.

Conclusions

RESET-PKD demonstrates that short-term KDIs potently induce ketogenesis and are feasible for ADPKD patients in daily life. While TLV quickly changed upon the onset of ketogenesis, changes in TKV may require longer-term interventions.
Infectious Complications of Abortion
Authors: Wall L Lewis , Yemane Awol
Published: November 2022

This article reviews the infectious complications of abortion (both spontaneous and induced) and the management of this condition. The key points are: (1) Making abortion illegal does not reduce its incidence or prevalence; rather, it only makes abortions unsafe, increasing the likelihood of infectious complications. (2) Timely recognition of developing sepsis in the pregnant patient is critical. This requires constant vigilance and a high index of suspicion. (3) Rapid intravenous administration of broad-spectrum antibiotics targeted to the likely intrauterine source of infection as soon as sepsis is diagnosed is critical to prevent severe sepsis, septic shock, and multisystem organ failure. (4) The mainstay of treatment is prompt evacuation of any residual products of conception from within the uterine cavity under broad-spectrum antibiotic cover targeting the likely intrauterine source of infection. (5) Prompt engagement of specialists in both critical care and obstetrics-gynecology is necessary to optimize outcomes in patients with septic abortion.
An usual case of bilateral deep venous thrombosis with associated pulmonary embolus
Authors: Plumptre Hannah , Giannoudi Marilena , Kurian John
Published: November 2022

Congenital absence of the inferior vena cava (IVC) triggers collateral vessel growth to drain the peripheries and abdominal organs. This causes venous stasis and increases the risk of deep vein thrombosis (DVT) and pulmonary embolism. Typically, patients with absent IVCs present before 30 years of age, with bilateral DVT symptoms triggered by intense exercise. The abnormality can remain undetected as computed tomography imaging is not usually performed. Due to the increased risk of clotting, these patients should be on life-long anticoagulation. Raising clinical awareness of this condition, to ensure appropriate investigations and treatment, is important.
Cannula removal with hemostasis secured by thoracoscopic support for accidental central vein puncture: a case report
Authors: Takamori Satoshi , Oizumi Hiroyuki , Nakamura Megumi , Suzuki Jun , Takeshi Akihiro , Shiono Satoshi
Published: November 2022

Central venous catheterization is a commonly used procedure for disease management. However, the procedure is not without risks of severe morbidity. We herein report hemostasis for accidental venous puncture using thoracoscopy. A 44-year-old man with short bowel syndrome and chronic renal failure required central venous catheterization for nutritional management and hemodialysis. Right internal jugular vein puncture was performed under ultrasonographic guidance, and the guidewire was inserted into the right atrium under fluoroscopic guidance. However, the operator inadvertently perforated the vein, and the thoracic cavity was entered while inserting the introducer. The patient’s vital signs were stable; therefore, we performed emergency surgery after computed tomography and achieved hemostasis through thoracoscopic surgery. Sufficient caution should be exercised while inserting central venous catheters through a thrombosed internal jugular vein. In some instances of catheter-induced vessel injury, combined surface and thoracoscopic hemostasis may be a reliable and minimally invasive management option.
Salmonella typhi: a rare cause of neck abscess
Authors: Doya Leen , Doya Lama , Ghanem Abdulmoniem
Published: November 2022

Salmonella typhi neck abscess represents a rare cause of focal salmonellosis. Most of the cases in the literature reviews were reported in immunosuppression adults; just two of them were in children. Herein we report a case of 7-year old healthy girl with a neck abscess caused by S. typhi. The patient was diagnosed according to serological and radiological findings. Incision and drainage of the abscess accompanied by broad-spectrum antibiotics were performed for treatments. S. typhi should be kept in mind as a cause of neck abscesses.
Primary splenic T-cell/histiocyte-rich B-cell lymphoma in a patient with recurrent hairy cell leukemia: a case report
Authors: Ahmad Tagrid Younes , Al Houri Hasan Nabil , Jomaa Sami , Assad Wisam , Addeen Sarah Zaher
Published: November 2022

T-cell/histiocyte-rich B-cell lymphoma is a high-grade, morphologic variant of diffuse large B-cell lymphoma. T-cell/histiocyte-rich B-cell lymphoma. It is rare as a primary splenic involvement and is usually reported as a second malignancy after hairy cell leukemia. Here, we report the first case that describes the occurrence of primary splenic T-cell/histiocyte-rich B-cell lymphoma in a patient with a previous diagnosis of recurrent hairy cell leukemia. A 53-year-old male patient was diagnosed with hairy cell leukemia in 1996 and achieved complete remission with Pentostatin. Then, recurrence of hairy cell leukemia was diagnosed in 2015 and treated with Cladribine. In 2016, he presented with B symptoms and hypersplenism. Therapeutic and diagnostic splenectomy was performed. Histopathological study with immunohistochemistry evaluation revealed the presence of T-cell/histiocyte-rich B-cell lymphoma. Therefore, second malignancies should be considered in patients with a previous neoplasm when symptoms recur or develop.
Nab-paclitaxel Followed by Dose-dense Epirubicin/Cyclophosphamide in Neoadjuvant Chemotherapy for Triple-negative Breast Cancer: A Phase II Study
Authors: Liu Yin , Fan Lei , Wang Zhong-Hua , Shao Zhi-Ming
Published: November 2022

Background

The anti-tumor activity of nab-paclitaxel followed by epirubicin/cyclophosphamide (EC) as neoadjuvant chemotherapy (NAC) in Asian patients remain unclear, particularly in the aggressive subtype triple-negative breast cancer (TNBC). This study aimed to evaluate the efficacy and safety of this NAC regimen in TNBC.

Methods

In this Simon’s two-stage, phase II study, treatment-naïve patients with unilateral primary invasive TNBC were enrolled. Eligible patients received nab-paclitaxel 125 mg/m2 weekly on day 1 for 12 weeks, followed by dose-dense EC (epirubicin 90 mg/m2; cyclophosphamide 600 mg/m2) on day 1 for four 2-week cycles. The primary endpoint was the total pathological complete response (tpCR, ypT0/is ypN0) rate.

Results

A total of 55 eligible patients were enrolled and treated. After NAC, tpCR and breast pathological complete response were respectively observed in 43.1% (95% CI, 29.3-57.8) and 49.0% (95% CI, 34.8-63.4) of 51 evaluable patients for pathological response evaluation. 44 had an objective response as their best response (80.0%; 95% CI, 67.0-89.6). No correlations between clinicopathological variables and pathological/clinical response were observed. Grade 3 or more adverse events (AEs) occurred in 63.6% of 55 patients. The most frequent AEs were alopecia. No treatment-related surgical delay or death occurred.

Conclusion

Nab-paclitaxel followed by dose-dense EC as NAC demonstrates promising anti-tumor activity and acceptable tolerability for patients with TNBC. (ClinicalTrials.gov Identifier: NCT03799679).
Mathematics: Method Without Metaphysics
Authors: Landry Elaine
Published: November 2022

I use my reading of Plato to develop what I call as-ifism, the view that, in mathematics, we treat our hypotheses as if they were first principles and we do this with the purpose of solving mathematical problems. I then extend this view to modern mathematics showing that when we shift our focus from the method of philosophy to the method of mathematics, we see that an as-if methodological interpretation of mathematical structuralism can be used to provide an account of the practice and the applicability of mathematics while avoiding the conflation of metaphysical considerations with mathematical ones.
Generalized disformal Horndeski theories: Cosmological perturbations and consistent matter coupling
Authors: Takahashi Kazufumi , Minamitsuji Masato , Motohashi Hayato
Published: November 2022

Invertible disformal transformations are a useful tool to investigate ghost-free scalar–tensor theories. By performing a higher-derivative generalization of the invertible disformal transformation on Horndeski theories, we construct a novel class of ghost-free scalar–tensor theories, which we dub generalized disformal Horndeski theories. Specifically, these theories lie beyond the quadratic/cubic DHOST class. We explore cosmological perturbations to identify a subclass where gravitational waves propagate at the speed of light and clarify the conditions for the absence of ghost/gradient instabilities for tensor and scalar perturbations. We also investigate the conditions under which a matter field can be consistently coupled to these theories without introducing unwanted extra degrees of freedom.
Mangrovimonas futianensis sp. nov., a novel species isolated from mangrove sediment
Authors: Yao Sijie , Yang Guiqin , Zhang Xueying , Lin Canfen , Zhuang Li
Published: November 2022

Three bacterial strains, designated as AS18T, AS27 and AS39, were obtained from mangrove sediment sampled in Futian district, Shenzhen, PR China. Cells of these strains were Gram-negative rods with no flagella. They were able to grow at 10–42 °C (optimum, 37 °C), at pH 5–9 (optimum, pH 6) and in 1–11 % (w/v) NaCl (optimum, 2 %). Phylogenetic analysis based on 16S rRNA gene sequences indicated that the new isolates were clustered within the genus

Mangrovimonas

, closely related to

Mangrovimonas yunxiaonensis

(95.1 % similarity) and

Mangrovimonas spongiae

(94.7 % similarity). Phylogenomic analysis based on multiple core genes revealed that the three strains were located in a different cluster from other closely related strains of the genus

Mangrovimonas

. Digital DNA–DNA hybridization, average nucleotide identity and average amino acid identity values calculated from genome sequences between isolates and type strains were lower than 25, 75 and 72 %, respectively. The dominant fatty acids were iso-C15 : 0 and iso-C15 : 1 G. The main respiratory quinone was identified as MK-6. The major polar lipids contained phosphatidylethanolamine, two unidentified aminolipids and five unidentified lipids. The results of multiphase taxonomy suggested that the three strains should be assigned to a novel species of the genus

Mangrovimonas

, for which the name Mangrovimonas futianensis sp. nov. is proposed, with the type strain AS18T (=GDMCC 1.2739T=JCM 34871T).
The chloroplast envelope localization of protoporphyrinogen oxidase 2 prevents full complementation of Arabidopsisppo1
Authors: Hedtke Boris , Strätker Sarah Melissa , Chiappe Pullido Andrea C. , Grimm Bernhard
Published: November 2022

All land plants encode two isoforms of protoporphyrinogen oxidase (PPO). While PPO1 is predominantly expressed in green tissues and its loss is seedling-lethal in Arabidopsis, the effects of PPO2 deficiency have not been investigated in detail. We identified twoppo2T-DNA insertion mutants from publicly available collections, one of which (ppo2-2) is a knock-out mutant. While the loss of PPO2 did not result in any obvious phenotype, significant changes in PPO activity were measured in etiolated and root tissues. However,ppo1ppo2double mutants are embryo-lethal. To shed light on possible functional differences between the two isoforms, PPO2 was overexpressed in theppo1background. Although theppo1phenotype was partially complemented, even strong overexpression of PPO2 was unable to fully compensate for the loss of PPO1. Analysis of its subcellular localization revealed that PPO2 is found exclusively in chloroplast envelopes, while PPO1 accumulates in thylakoid membranes. A mitochondrial localization of PPO2 in Arabidopsis was ruled out. SinceA. thaliana PPO2does not encode a cleavable transit peptide, integration of the protein into the chloroplast envelope must make use of a non-canonical import route. However, when a chloroplast transit peptide was fused to the N-terminus of PPO2, the enzyme was detected predominantly in thylakoid membranes, and was able to fully complementppo1. Thus, the two PPO isoforms in Arabidopsis are functionally equivalent, but spatially separated. Their distinctive localizations within plastids thus enable the synthesis of discrete sub-pools of the PPO product protoprophyrin IX, which may serve different cellular needs.
An Early SARS-CoV-2 Omicron Outbreak in a Dormitory in Saint-Petersburg, Russia
Authors: Klink Galya V. , Danilenko Daria M. , Komissarov Andrey B. , Yolshin Nikita , Shneider Olga V. , Shcherbak Sergey , Nabieva Elena , Shvyrev Nikita , Konovalova Nadezhda , Zheltukhina Alyona , Fadeev Artem , Komissarova Kseniya , Ksenafontov Andrey , Musaeva Tamila , Eder Veronica , Pisareva Maria , Nekrasov Petr , Shchur Vladimir , Bazykin Georgii A. , Lioznov Dmitry
Published: November 2022

The Omicron variant of SARS-CoV-2 has rapidly spread globally in late 2021 - early 2022, displacing the previously prevalent Delta variant. Before December 16, 2021, community transmission had already been observed in tens of countries globally. However, in Russia, the majority of reported cases at that time had been sporadic and associated with travel. Here, we report an Omicron outbreak at a student dormitory in Saint Petersburg between December 16 - 29, 2021, which was the earliest known instance of large-scale community transmission in Russia. Out of the 465 sampled residents of the dormitory, 180 (38.7%) tested PCR positive. Among the 118 residents for whom the variant has been tested by whole-genome sequencing, 111 (94.1%) carried the Omicron variant. Among these 111 residents, 60 (54.1%) were vaccinated or had reported previous COVID-19. Phylogenetic analysis confirmed that the outbreak was caused by a single introduction of the BA.1.1 sublineage of Omicron. The dormitory-derived clade constituted a significant proportion of BA.1.1 samples in Saint-Petersburg and has spread to other regions of Russia and other countries. The rapid spread of Omicron in a population with preexisting immunity to previous variants underlines its propensity for immune evasion.
ArabidopsisORP2A positively regulates glucose signaling by interacting with AtRGS1 and promoting AtRGS1 degradation
Authors: Yu Qian , Zou Wenjiao , Liu Kui , Sun Jialu , Chao Yanru , Sun Mengyao , Zhang Qianqian , Wang Xiaodong , Wang Xiaofei , Ge Lei
Published: November 2022

Heterotrimeric GTP-binding proteins (G proteins) are a group of regulators essential for signal transmission into cells. AtRGS1 (Regulator of G protein Signaling 1) with intrinsic GTPase-accelerating protein (GAP) activity could suppress G protein and glucose signal transduction inArabidopsis. However, how AtRGS1 activity is regulated is currently poor understood. Here we identified a knockout mutantorp2a-1(oxysterol-binding protein(OSBP)-related protein 2A) which shows phenotypes similar toagb1-2(arabidopsis g-protein beta 1). With overexpression of ORP2A, transgenic lines display short hypocotyl, hypersensitivity to sugar and lower intracellular AtRGS1 level than control. Consistently, ORP2A shows interaction with AtRGS1in vitroandvivo. Tissue specificity of ORP2A with two alternative protein forms imply its functions in organ size and shape controlling. Bioinformatic data and phenotypes oforp2a-1, agb1-2and double mutant reveal genetic interactions in the regulation of G protein signaling and sugar response between ORP2A and Gβ. Both alternative splicing forms of ORP2A locate in the ER, PM (Plasma Membrane) and EPCS (ER-PM Contact Sites), and interact with VAP27-1 mediated by a FFAT-like motifin vivoandvitro. ORP2A also displays differential phosphatidyl phosphoinositide binding activity mediated by its PH domain invitro. Taken together, it is suggested thatArabidopsismembrane protein ORP2A interacts with AtRGS1 and VAP27-1 to positively regulate G protein and sugar signaling by facilitating AtRGS1 degradation.
Differential leaf flooding resilience inArabidopsis thalianais controlled by age-dependent ORESARA1 activity
Authors: Rankenberg Tom , van Veen Hans , Sedaghatmehr Mastoureh , Liao Che-Yang , Devaiah Muthanna Biddanda , Balazadeh Salma , Sasidharan Rashmi
Published: November 2022

The volatile phytohormone ethylene is a major regulator of plant adaptive responses to flooding. In flooded plant tissues, it quickly increases to high concentrations due to its low solubility and diffusion rates in water. The passive, quick and consistent accumulation of ethylene in submerged plant tissues makes it a reliable cue to trigger flood-acclimative responses, including metabolic adjustments to cope with flood-induced hypoxia. However, persistent ethylene accumulation also accelerates leaf senescence. Stress-induced senescence hampers the photosynthetic capacity and stress recovery. In submergedArabidopsisshoots, senescence follows a strict age-dependent pattern starting with the older leaves. Although mechanisms underlying ethylene-mediated senescence have been uncovered, it is unclear how submerged plants avoid an indiscriminate breakdown of leaves despite high systemic ethylene accumulation. Here we demonstrate inArabidopsisplants that even though submergence triggers a leaf-age independent activation of ethylene signaling via EIN3, senescence was initiated only in the old leaves, and independent of the N-degron pathway of oxygen sensing. This EIN3 stabilization also led to the overall transcript and protein accumulation of the senescence-promoting transcription factor ORESARA1 (ORE1). ORE1 protein accumulated in both old and young leaves during submergence. However, leaf age-dependent senescence could be explained by ORE1 protein activation specifically in old leaves, independent of the previously identified age-dependent control ofORE1via miR164. Our results unravel a mechanism by which plants regulate the speed and pattern of senescence during environmental stresses like flooding. The age-dependent activity of ORE1 ensures that older expendable leaves are dismantled first, thus prolonging the life of younger leaves and meristematic tissues vital to whole plant survival.

Significance statement

Flooded plants systemically accumulate saturating concentrations of the senescence promoting volatile hormone ethylene. Yet, leaf senescence follows a strict age-dependent gradient, thus prolonging the survival of young leaves and meristematic tissue. Here we show that in flooded plants, age-independent activation of ethylene signaling via EIN3, induces the systemic accumulation of the senescence-inducing transcription factor ORE1. Premature senescence of younger tissues is prevented by the posttranslational activation of ORE1 specifically in old leaves, where it induces the transcription of senescence-associated genes. Our results highlight how a systemic stress signal (ethylene accumulation upon flooding) induces a signaling cascade that diverges in an age-dependent manner, and eventually leads to an age-dependent physiological output (leaf senescence).
Survivor bias drives overestimation of stability in reconstructed ancestral proteins
Authors: Thomas Adam , Evans Benjamin D. , van der Giezen Mark , Harmer Nicholas J.
Published: November 2022

Ancestral sequence reconstruction has been broadly employed over the past two decades to probe the evolutionary history of life. Many ancestral sequences are thermostable, supporting the “hot-start” hypothesis for life’s origin. Recent studies have observed thermostable ancient proteins that evolved in moderate temperatures. These effects were ascribed to “consensus bias”. Here, we propose that “survivor bias” provides a complementary rationalisation for ancestral protein stability in alignment-based methods. As thermodynamically unstable proteins will be selected against, ancestral or consensus sequences derived from extant sequences are selected from a dataset biased towards the more stabilising amino acids in each position. We thoroughly explore the presence of survivor bias using a highly parameterizablein silicomodel of protein evolution that tracks stability at the population, protein, and amino acid levels. We show that ancestors and consensus sequences derived from populations evolved under selective pressure for stability throughout their history are significantly biased toward thermostability. Our work proposes a complementary explanation of the origin of thermostability in the burgeoning engineering tools of ancestral sequence reconstruction and consensuses. It provides guidance for the thorough derivation of conclusions from future ancestral sequence reconstruction work.
Patterns of genetic differentiation imply distinct evolutionary histories of the sibling mosquito speciesAnopheles messeaeandAnopheles daciaein Eurasia
Authors: Brusentsov Ilya I. , Gordeev Mikhail I. , Yurchenko Andrey A. , Karagodin Dimitriy A. , Moskaev Anton V. , Hodge James M. , Burlak Vladimir A. , Artemov Gleb N. , Sibataev Anuarbek K. , Becker Norbert , Sharakhov Igor V. , Baricheva Elina M. , Sharakhova Maria V.
Published: November 2022

Detailed knowledge of phylogeography is important for control of mosquito species involved in transmission of human infectious diseases.Anopheles messeaeis a geographically widespread and genetically diverse dominant vector of malaria in Eurasia. A closely related sibling species,An. daciae, was distinguished fromAn. messeaebased on a few nucleotide differences in its ribosomal DNA. However, the mechanisms of speciation and their evolutionary histories are poorly understood. Here, we performed a large-scale population genetics analysis of 3694 mosquitos from Eurasia to understand the species divergence, diversity, and population structure using the Internal Transcribed Spacer 2 of ribosomal DNA for species identification and frequencies of 11 polymorphic chromosomal inversions as genetic markers. The study revealed striking differences in the geographical distribution of the sibling species. The largest genetic differences betweenAn. messeaeandAn. daciaewere detected in the X sex chromosome suggesting that this chromosome plays a role in speciation. The frequencies of autosomal inversions differed significantly between the species, strongly supporting a restricted gene flow. The clinal variability of some inversion frequencies was revealed in both species implicating their possible involvement in climate adaptations. Statistical analysis of inversion polymorphism clearly distinguished two clusters associated with the two species and demonstrated much higher genetic diversity withinAn. messeae. Overall, the frequencies of hybrids in all locations were extremely low with the exception of several southeastern populations, where putative hybrids were abundant. Thus, the pattern of genetic differentiation implies dramatic differences in geographic distribution, population structure, and evolutionary histories of the sibling speciesAn. messeaeandAn. daciae.
Simulation-based assessment of the performance of hierarchical abundance estimators for camera trap surveys
Authors: Martijn Bollen , Jim Casaer , Natalie Beenaerts , Thomas Neyens
Published: November 2022

The need for knowledge about abundance to guide conservation and management strategies in combination with low detectability of many species has led to a widespread use in ecology and management of a range of hierarchical models (HMs) for abundance. These models also appear like good candidates for inference about local abundance in nature reserves studied by camera traps. However, the best choice among these models is unclear, particularly how they perform in the face of several complicating features of realistic populations that include: (i) movements relative to sites, (ii) multiple detections of unmarked individuals within a single survey, and (iii) low probabilities of detection. We conducted a simulation-based comparison of three HMs (Royle-Nichols, binomial N-mixture and Poisson N-mixture model) in the context of small populations of elusive animals in a single study area, where animals cannot be distinguished individually and hence double counting occurs. We generated count data by simulating camera traps monitoring individuals moving according to a Gaussian random walk. Under the simulated scenarios none of the three HMs yielded accurate abundance estimates. Moreover, the performance of each HM depended on the interpretation of abundance. By pooling abundance estimates for trend estimation, each models’ performance markedly improves. Overall, the Royle-Nichols and Poisson N-mixture models outperform a binomial N-mixture model. This emphasizes the importance of choosing the appropriate HM for the data problem.
Pattern formation and travelling waves in a multiphase moving boundary model of tumour growth
Authors: Jepson Jacob M. , O’Dea Reuben D. , Billingham John , Fadai Nabil T.
Published: November 2022

We analyse a multiphase, moving boundary model that describes solid tumour growth. We consider the evolution of a motile, viscous cell phase and an inviscid extracellular liquid phase. The model comprises two partial differential equations that govern the cell volume fraction and the cell velocity, together with a moving boundary condition for the tumour edge. Numerical simulations of the model indicate that patterned solutions can be obtained, which correspond to multiple regions of high cell density separated by regions of low cell density. In other parameter regimes, solutions of the model can develop into a forward- or backward-moving travelling wave, corresponding to tumour growth or extinction, respectively. A travelling-wave analysis allows us to find the corresponding wave speed, as well as criteria for the growth or extinction of the tumour. Furthermore, a stability analysis of these travelling-wave solutions provides us with criteria for the occurrence of patterned solutions. Finally, we discuss how the initial cell distribution, as well as parameters related to cellular motion and cell-liquid drag, control the qualitative features of patterned solutions.
Immune engineered extracellular vesicles to modulate T cell activation in the context of type 1 diabetes
Authors: Becker Matthew W. , Peters Leeana D. , Myint Thinzar , Brusko Todd M. , Phelps Edward A.
Published: November 2022

Extracellular vesicles (EVs) are small, biologically active, cell-secreted vesicles that can affect immune responses through antigen presentation and co-stimulation or co-inhibition. We generated designer EVs to modulate autoreactive T cells in the context of type 1 diabetes by engineering K562 cells to express HLA-A*02 (HLA-A2) alongside co-stimulatory CD80 and/or co-inhibitory PD-L1. EVs presenting HLA-A2 and CD80 activated CD8+T cells in a dose, antigen, and HLA-specific manner. Adding PD-L1 to these EVs produced an immunoregulatory response, reducing CD8+T cell activation and cytotoxicityin vitro. EVs alone could not stimulate T cells without antigen presenting cells (APCs), suggesting that EVs act by cross-dressing APCs. EVs lacking CD80 were ineffective at modulating CD8+T cell activation, suggesting that both peptide-HLA complex and costimulatory molecules are required for EV-mediated immune modulation through APC cross-dressing. These results provide mechanistic insight into the rational design of EVs as a cell-free, yet precision medicine-based approach to immunotherapy that can be tailored to promote antigen-specific immune tolerance or pro-inflammatory responses.
The impact of functional correlations on task information coding
Authors: Ito Takuya , Murray John D.
Published: November 2022

State-dependent neural correlations can be understood from a neural coding framework. Noise correlations – trial-to-trial or moment-to-moment co-variability – can be interpreted only if the underlying signal correlation – similarity of task selectivity between pairs of neural units – is known. Despite many investigations in local spiking circuits, it remains unclear how this coding framework applies to large-scale brain networks. Here we investigated relationships between large-scale noise correlations and signal correlations in a multi-task human fMRI dataset. We found that task-state noise correlation changes (e.g., functional connectivity) did not typically change in the same direction as their underlying signal correlation (e.g., tuning similarity of two regions). This suggests that 1) trial-by-trial variability typically decreases between similarly tuned regions, and 2) stimulus-driven activity does not linearly superimpose atop the network’s background activity. Crucially, noise correlations that changed in the opposite direction as their signal correlation (i.e., anti-aligned correlations) improved information coding of these brain regions. In contrast, noise correlations that changed in the same direction (aligned noise correlations) as their signal correlation did not. Interestingly, these aligned noise correlations were primarily correlation increases, suggesting that most functional correlation increases across fMRI networks actually degrade information coding. These findings illustrate that state-dependent noise correlations shape information coding of functional brain networks, with interpretation of correlation changes requiring knowledge of underlying signal correlations.
Hierarchical Modular Structure of the Drosophila Connectome
Authors: Kunin Alexander B. , Guo Jiahao , Bassler Kevin E. , Pitkow Xaq , Josić Krešimir
Published: November 2022

The structure of neural circuitry plays a crucial role in brain function. Previous studies of brain organization generally had to trade off between coarse descriptions at a large scale and fine descriptions on a small scale. Researchers have now reconstructed tens to hundreds of thousands of neurons at synaptic resolution, enabling investigations into the interplay between global, modular organization, and cell type-specific wiring. Analyzing data of this scale, however, presents unique challenges. To address this problem we applied novel community detection methods to analyze the synapse-level reconstruction of an adult fruit fly brain containing over 20 thousand neurons and 10 million synapses. Using a machine-learning algorithm, we find the most densely connected communities of neurons by maximizing a generalized modularity density measure. We resolve the community structure at a range of scales, from large (on the order of thousands of neurons) to small (on the order of tens of neurons). We find that the network is organized hierarchically and larger-scale communities are composed of smaller-scale structures. Our methods identify well-known features of the fly brain, including its sensory pathways. Moreover, focusing on specific brain regions, we are able to identify subnetworks with distinct connectivity types. For example, manual efforts have identified layered structures in the fan-shaped body. Our methods not only automatically recover this layered structure, but also resolve finer connectivity patterns to downstream and upstream areas. We also find a novel modular organization of the superior neuropil, with distinct clusters of upstream and downstream brain regions dividing the neuropil into several pathways. These methods show that the fine-scale, local network reconstruction made possible by modern experimental methods are sufficiently detailed to identify the organization of the brain across scales, and enable novel predictions about the structure and function of its parts.
Predicting Gastrointestinal Absorption of Prodrugs and their Drugs with the ANDROMEDA by Prosilico Software
Authors: Fagerholm Urban , Hellberg Sven , Alvarsson Jonathan , Spjuth Ola
Published: November 2022

Abstract

Introduction

Some prodrugs are developed in order to improve gastrointestinal absorption properties such as permeability and solubility/dissolution. Prediction of the uptake of prodrugs and their drugs is challening for reasons including gastrointestinal hydrolysis and active transport.

Objective and Methodology

The objective was to use the ANDROMEDA software by Prosilico to predict absorption characteristics - passive fraction absorbed (fa,passive), dose-adjusted dissolution potential (fdiss) and total fa(fa) - of prodrugs and their drugs (including drugs and their active metabolites), and to evaluate how they differ between prodrugs and drugs and the predictive accuracy of the software.

Results

70 prodrug-drug pairs were found and selected for the study. The mean predicted fa,passiveand fdissfor the prodrugs were 0.74 and 0.94, respectively. Corresponding estimates for the drugs were 0.72 and 0.98, respectively. For non-hydrolyzed prodrugs, the median relative and absolute prediction errors for fawere 1.17-fold and 0.08, respectively. Corresponding values for drugs were 1.11-fold and 0.07, respectively. The correlation between predicted and observed fafor non-hydrolyzed ester prodrugs and drugs combined (predictive accuracy) was 0.6.

Conclusion

Prodrugs and drugs had similar average predicted fa,passiveand fdiss, and most had or were predicted to have at least 50 % fa. The fafor about 1/3 of non-hydrolyzed prodrugs was higher than for corresponding drugs, showing successful prodrug design. Adequate prediction accuracy validates ANDROMEDA for prediction of prodrug and drug absorption in man.
Micromagnetic Stimulation (μMS) Dose-Response of the Rat Sciatic Nerve
Authors: Saha Renata , Sanger Zachary , Bloom Robert , Benally Onri J. , Wu Kai , Tonini Denis , Low Walter C. , Keirstead Susan A. , Netoff Theoden I. , Wang Jian-Ping
Published: November 2022

Objective

The objective of this study was to investigate the effects of micromagnetic stimuli strength and frequency from theMagneticPen(MagPen) on the rat right sciatic nerve. The nerve’s response would be measured by recording muscle activity and movement of the right hind limb.

Approach

The MagPen was custom-built such that it can be held over the sciatic nerve in a stable manner. Rat leg muscle twitches were captured on video and movements were extracted using image processing algorithms. EMG recordings were also used to measure muscle activity.

Main results

The MagPen prototype when driven by alternating current, generates time-varying magnetic field which as per Faraday’s Law of Electromagnetic Induction, induces an electric field for neuromodulation. The orientation dependent spatial contour maps for the induced electric field from the MagPen prototype has been numerically simulated. Furthermore, in thisin vivowork on μMS, a dose-response relationship has been reported by experimentally studying how the varying amplitude (Range: 25 mVp-pthrough 6 Vp-p) and frequency (Range: 100 Hz through 5 kHz) of the MagPen stimuli alters the hind limb movement. The primary highlight of this dose-response relationship is that at a higher frequency of the μMS stimuli, significantly smaller amplitudes can trigger hind limb muscle twitch. This frequency-dependent activation can be justified following directly from the Faraday’s Law as the magnitude of the induced electric field is directly proportional to frequency.

Significance

This work reports that μMS can successfully activate the sciatic nerve in a dose-dependent manner. The MagPen probe, unlike electrodes, does not have a direct electrochemical interface with tissues rendering it much safer than an electrode. Magnetic fields create more precise activation than electrodes because they induce smaller volumes of activation. Finally, unique features of μMS such as orientation dependence, directionality and spatial selectivity have been demonstrated.
A preclinical model of THC edibles that produces high-dose cannabimimetic responses
Authors: English Anthony , Uittenbogaard Fleur , Torrens Alexa , Sarroza Dennis , Slaven Anna , Piomelli Danielle , Bruchas Michael R. , Stella Nephi , Land Benjamin B.
Published: November 2022

No preclinical experimental approach enables the study of voluntary oral consumption of high-concentration Δ9-tetrahydrocannabinol (THC) and its intoxicating effects, mainly owing to the aversive response of rodents to THC that limits intake. Here we developed a palatable THC formulation and an optimized access paradigm in mice to drive voluntary consumption. THC was formulated in chocolate gelatin (THC-E-gel). Adult male and female mice were allowedad libitumaccess for 1 and 2 h. Cannabimimetic responses (hypolocomotion, analgesia, and hypothermia) were measured following access. Levels of THC and its metabolites were measured in blood and brain tissue. Acute acoustic startle responses were measured to investigate THC-induced psychotomimetic behavior.

When allowed access for 2 h to THC-E-gel on the second day of a three-day exposure paradigm, adult mice consumed up to ≈30 mg/kg over 2 h which resulted in robust cannabimimetic behavioral responses (hypolocomotion, analgesia and hypothermia). Consumption of the same gelatin decreased on the following 3rdday of exposure. Pharmacokinetic analysis show that THC-E-gel consumption led to parallel accumulation of THC and its psychoactive metabolite, 11-OH-THC, in brain, a profile that contrasts with the known rapid decline in brain 11-OH-THC levels following THC intraperitoneal (i.p.) injections. THC-E-gel consumption increased the acoustic startle response in males but not in females, demonstrating a sex-dependent effect of consumption. Thus, while voluntary consumption of THC-E-gel triggered equivalent cannabimimetic responses in male and female mice, it potentiated acoustic startle responses preferentially in males. We build a dose-prediction model that included cannabimimetic behavioral responses elicited byi.p.versus THC-E-gel to test the accuracy and generalizability of this experimental approach and found that it closely predicted the measured acoustic startle results in males and females. In summary, THC-E-gel offers a robust preclinical experimental approach to study cannabimimetic responses triggered by voluntary consumption in mice, including sex-dependent psychotomimetic responses.
More than just axons: A positive relationship between an intracellular isotropic diffusion signal and pubertal development in white matter regions in a massive adolescent cohort
Authors: Newman Benjamin T. , Patrie James T. , Druzgal T. Jason
Published: November 2022

Puberty is a key event in adolescent development that involves significant, hormone-driven changes to many aspects of physiology including the brain. Understanding how the brain responds during this time period is important for evaluating neuronal developments that affect mental health throughout adolescence and the adult lifespan. This study examines diffusion MRI scans from the cross-sectional ABCD Study baseline cohort, a large multi-site study containing thousands of participants, to describe the relationship between pubertal development and brain microstructure. Using advanced, 3-tissue constrained spherical deconvolution methods, this study is able to describe multiple tissue compartments beyond only white matter (WM) axonal qualities. After controlling for age, sex, brain volume, subject handedness, scanning site, and sibling relationships, we observe a positive relationship between an isotropic, intracellular diffusion signal fraction and pubertal development across a majority of regions of interest (ROIs) in the WM skeleton. We also observe regional effects from an intracellular anisotropic signal fraction compartment and extracellular isotropic free water-like compartment in several ROIs. This work suggests that changes during pubertal development elicit a complex response from brain tissue that cannot be completely described by traditional methods focusing only on WM axonal properties. This work brings in vivo human neuroimaging studies more into line with work performed on animal models, which describe an interaction between increased myelination, neurogenesis, angiogenesis, and glial cell proliferation in response to pubertal hormones.
Effect of tRNA maturase depletion on the levels and stabilities of ribosome assembly cofactor mRNAs inBacillus subtilis
Authors: Trinquier Aude , Condon Ciarán , Braun Frédérique
Published: November 2022

The impact of translation on mRNA stability can be varied, ranging from a protective effect of ribosomes that shield mRNA from ribonucleases (RNases), to preferentially exposing sites of RNase cleavage. These effects can change depending on whether ribosomes are actively moving along the mRNA or whether they are stalled at particular sequences, structures or awaiting charged tRNAs. We recently observed that depletingB. subtiliscells of its tRNA maturation enzymes RNase P or RNase Z, led to altered mRNA levels of a number of assembly factors involved in the biogenesis of the 30S ribosomal subunit. Here, we extend this study to other assembly factor mRNAs and identify multiple transcriptional and translational layers of regulation of therimMoperon mRNA that occur in response to the depletion of functional tRNAs.

Importance

The passage of ribosomes across individual mRNAs during translation can have different effects on their degradation, ranging from a protective effect by shielding from ribonucleases, to in some cases, making the mRNA more vulnerable to RNase action. We recently showed that some mRNAs coding for proteins involved in ribosome assembly were highly sensitive to the availability of functional tRNA. Using strains depleted for the major tRNA processing enzymes RNase P and RNase Z, we expanded this observation to a wider set of mRNAs, including some unrelated to ribosome biogenesis. We characterize the impact of tRNA maturase depletion on therimMoperon mRNA and show it is highly complex, with multiple levels of transcriptional and post-transcriptional effects coming into play.
CURATE.AI – AI-derived personalized tacrolimus dosing for pediatric liver transplant: A retrospective study
Authors: Tan Shi-Bei , Kumar Kirthika Senthil , Gan Tiffany Rui Xuan , Truong Anh T. L. , Tan Lester W. J. , Blasiak Agata , Mali Vidyadhar Padmakar , Aw Marion M. , Ho Dean
Published: November 2022

Tacrolimus is the cornerstone of immunosuppressive therapy after pediatric liver transplantation. However, reliance on the physician’s experience for dose titration, coupled with tacrolimus’s narrow therapeutic window and inter and intra-patient variability, often results in frequent under or over-dosing with detrimental patient outcomes. Existing predictive dose personalization models are not readily feasible for clinical implementation, as they require multiple measurements each day while the standard frequency is once daily. We developed CURATE.AI, a small-data artificial intelligence-derived platform, as a clinical decision support system to personalize doses using the patient’s own data obtained once a day. Retrospective dose personalization with CURATE.AI on 16 patients’ data demonstrated potential to enable patients to stay in the therapeutic range longer and reach the therapeutic range significantly earlier. Our findings support the testing of CURATE.AI in a prospective controlled trial as an aid for the physician’s decision on tacrolimus dose personalization after pediatric liver transplantation.
Inhibition of MLKL impairs abdominal aortic aneurysm development by attenuating smooth muscle cell necroptosis
Authors: Nemade Harshal N , Mehrkens Dennis , Lottermoser Hannah Sophia , Yilmaz Zeynep Ece , Schelemei Patrick , Picard Felix Ruben , Geißen Simon , Schwab Gülsah Fülgen , Hoyer Friedrich Felix , Guthoff Henning , Hof Alexander , Nettersheim Felix Sebastian , Sachinidis Agapios , Winkels Holger , Baldus Stefan , Pasparakis Manolis , Adam Matti , Mollenhauer Martin
Published: November 2022

Background

Receptor-interacting serine/threonine-protein kinase 1 and 3 (RIPK1 and RIPK3) dependent cell death has been identified as a crucial mediator of abdominal aortic aneurysm (AAA) development. RIPK3 mediates phosphorylation of Mixed lineage kinase domain like pseudokinase (MLKL) thereby inducing its oligomerization and translocation to the cell membrane. Given the dual role of RIPKs being involved in necroptosis as well as in apoptosis induction, the specific role of MLKL-induced necroptotic cell death in AAA remains unclear.

Methods

We monitored elastase-perfusion (PPE) induced progression of AAA in C57BL/6N (WT), RIPK1 kinase-inactive (Ripk1D138N/D138N), MLKL knockout (Mlkl−/−) and MLKL phospho-deficient (MlklAA) mice by ultrasound measurements, histological analyses and bulk mRNA sequencing to assess structural and molecular aortic changes. Bone marrow transplantations in WT andMlklAAmice were utilized to dissect the role of MLKL in smooth muscle cells (SMCs) and myeloid cells in AAA development. MLKL expressing human SMCs were generated to investigate necroptosis-induced proinflammatory cytokine secretion and subsequent polymorphonuclear neutrophil (PMN) migration and activation in vitro.

Results

Ultrasound analysis showed that ~70% of the WT animals developed PPE induced-AAA with significant aortic structural alterations and enhanced myeloid cell infiltration. In contrast,Ripk1D138N/D138N,MlklAA, andMlkl−/−mice were protected from AAA. This protection was associated with reduced adverse extracellular matrix (ECM) remodeling and leukocyte infiltration. MLKL deficiency was associated with a significant downregulation of genes involved in fibrinolysis, anti-inflammatory response, immune response and complement activation in aortic tissue in AAA. Bone marrow transplantation studies showed the lack of MLKL in SMCs to be the main driver of AAA protection. Proinflammatory cytokine secretion was elevated in necroptosis induced SMCs and resulted in a significant accumulation and activation of PMN.

Conclusions

Overall, these findings indicate that MLKL-induced necroptotic SMC death and subsequent proinflammatory leukocyte activation play a causative role in AAA development and suggest that pharmacological inhibition of MLKL may represent a promising treatment strategy for AAA disease.