bluuebunny/crossref_metadata_2025 huggingface dataset:
Sensitization of FOLFOX-resistant colorectal cancer cells via the modulation of a novel pathway involving protein phosphatase 2A
Authors: Narayan Satya , Raza Asif , Mahmud Iqbal , Koo Nayeong , Garrett Timothy J. , Law Mary E. , Law Brian K. , Sharma Arun K.
Published: July 2021

The treatment of colorectal cancer (CRC) with FOLFOX shows some efficacy, but these tumors quickly develop resistance to this treatment. We have observed an increased phosphorylation of AKT1/mTOR/4EBP1 and levels of p21 in FOLFOX-resistant CRC cells. We have identified a small molecule, NSC49L, that stimulates protein phosphatase 2A (PP2A) activity, downregulates the AKT1/mTOR/4EBP1-axis, and inhibits p21 translation. We have provided evidence that NSC49L- and TRAIL-mediated sensitization is synergistically induced in p21-knockdown CRC cells, which is reversed in p21-overexpressing cells. p21 binds with procaspase 3 and prevents activation of caspase 3. We have shown that TRAIL induces apoptosis through the activation of caspase 3 by NSC49L-mediated downregulation of p21 translation, and thereby cleavage of procaspase 3 into caspase 3. NSC49L does not affect global protein synthesis. These studies provide a mechanistic understanding of NSC49L as a PP2A agonist, and how its combination with TRAIL sensitizes FOLFOX-resistant CRC cells.

Graphical Abstract
Drop, Swap, and Generate: A Self-Supervised Approach for Generating Neural Activity
Authors: Liu Ran , Azabou Mehdi , Dabagia Max , Lin Chi-Heng , Azar Mohammad Gheshlaghi , Hengen Keith B. , Valko Michal , Dyer Eva L.
Published: July 2021

Meaningful and simplified representations of neural activity can yield insights into how and what information is being processed within a neural circuit. However, without labels, finding representations that reveal the link between the brain and behavior can be challenging. Here, we introduce a novel unsupervised approach for learning disentangled representations of neural activity called Swap-VAE. Our approach combines a generative modeling framework with an instance-specific alignment loss that tries to maximize the representational similarity between transformed views of the input (brain state). These transformed (or augmented) views are created by dropping out neurons and jittering samples in time, which intuitively should lead the network to a representation that maintains both temporal consistency and invariance to the specific neurons used to represent the neural state. Through evaluations on both synthetic data and neural recordings from hundreds of neurons in different primate brains, we show that it is possible to build representations that disentangle neural datasets along relevant latent dimensions linked tso behavior.
Discriminative and affective touch converge: Somatosensory cortex represents Aß input in a CT-like manner
Authors: Schirmer Annett , Lai Oscar , McGlone Francis , Cham Clare , Lau Darwin
Published: July 2021

Current theory divides the human mechanical sense into discriminative and affective systems. A discriminative system supports tactile exploration and manipulation via fast Aß signaling, whereas an affective system supports the pleasure of friendly interpersonal touch via slow CT signaling. To probe this system segregation, we recorded the electroencephalogram from participants being stroked and reporting stroke pleasantness. We observed a somatosensory negativity that was maximal for CT optimal as compared with sub-optimal velocities, that predicted subjective pleasantness, and showed only for stroking of hairy skin known to be CT innervated. Importantly, the latency of this negativity preceded C fiber input to the brain by several hundred milliseconds and is best explained by interactions between CT and Aß processes in the spinal cord. Our data challenge the divide between discriminative and affective touch implying instead that both fast Aß and slow CT signaling play an important role in tactile pleasure.
High-throughput Mutational Surveillance of the SARS-CoV-2 Spike Gene
Authors: Özkan Ezgi , Strobl Marcus Martin , Novatchkova Maria , Yelagandula Ramesh , Albanese Tanino Guiseppe , Triska Petr , Endler Lukas , Penz Thomas , Patocka Timothej , Felsenstein Vera , Vogt Alexander , Tamir Ido , Seitz Tamara , Födinger Manuela , Herwig Ralf , Indra Alexander , Schmid Daniela , Bock Christoph , Bergthaler Andreas , Stark Alexander , Allerberger Franz , Elling Ulrich , Cochella Luisa
Published: July 2021

SARS-CoV-2 has evolved rapidly towards higher infectivity and partial immune escape over the course of the pandemic. This evolution is driven by the enormous virus population, that has infected close to 200 million people by now. Therefore, cost effective and scalable methods are needed to monitor viral evolution globally. Mutation-specific PCR approaches have become inadequate to distinguish the variety of circulating SARS-CoV-2 variants and are unable to detect novel ones. Conversely, whole genome sequencing protocols remain too labor- and cost-intensive to monitor SARS-CoV-2 at the required density. By adapting SARSeq we present a simple, fast, and scalable S-gene tiling pipeline for focused sequencing of the S-gene encoding for the spike protein. This method reports on all sequence positions with known importance for infectivity and immunity, yet scales to >20K samples per run. S-gene tiling is used for nationwide surveillance of SARS-CoV-2 at a density of 10% to 50% of all cases of infection in Austria. SARSeq S-tiling uncovered several infection clusters with variants of concern such as the biggest known cluster of Beta/B.1.351 outside Africa and successfully informed public health measures in a timely manner, allowing their successful implementation. Our close monitoring of mutations further highlighted evolutionary constraints and freedom of the spike protein ectodomain and sheds light on foreseeable evolutionary trajectories.
The human vestibular cortex: functional anatomy, connectivity and the effect of vestibular disease
Authors: Ibitoye Richard T. , Mallas Emma-Jane , Bourke Niall J. , Kaski Diego , Bronstein Adolfo M. , Sharp David J.
Published: July 2021

Area OP2 in the posterior peri-sylvian cortex has been proposed to be the core human vestibular cortex. We defined the functional anatomy of OP2 using spatially constrained independent component analysis of functional MRI data from the Human Connectome Project. Ten distinct subregions were identified. Most subregions showed significant connectivity to other areas with vestibular function: the parietal opercula, the primary somatosensory cortex, the supracalcarine cortex, the left inferior parietal lobule and the anterior cingulate cortex. OP2 responses to vestibular and visual-motion were analysed in 17 controls and 17 right-sided unilateral vestibular lesion patients (vestibular neuritis) who had previously undergone caloric and optokinetic stimulation during functional MRI. In controls, a posterior part of right OP2 showed: (a) direction-selective responses to visual motion; and (b) activation during caloric stimulation that correlated positively with perceived self-motion, and negatively with visual dependence. Patients showed abnormal OP2 activity, with an absence of visual or caloric activation of the healthy ear and no correlations with dizziness or visual dependence – despite normal brainstem responses to caloric stimulation (slow-phase nystagmus velocity). A lateral part of right OP2 showed activity that correlated with chronic dizziness (situational vertigo) in patients. Our results define the functional anatomy of OP2 in health and disease. A posterior subregion of right OP2 shows strong functional connectivity to other vestibular regions and a visuo-vestibular profile that becomes profoundly disrupted after vestibular disease. In vestibular patients, a lateral subregion of right OP2 shows responses linked to the challenging long-term symptoms which define poorer clinical outcomes.

Significance statement

The human cortical vestibular network is critical to higher vestibular functions such as the perception of self-motion, judgements about verticality (‘which way is up’), and adaptation following peripheral vestibular disease (e.g. vestibular neuritis). The functional organisation of this network has remained poorly understood. In this study, we define the functional anatomy of area OP2 - a core region within the human cortical vestibular network. We identify subregions of OP2 with strong connectivity to other cortical vestibular areas. We show specific subregions of right OP2 process vestibular and visual motion information in health and that such processing is disrupted following peripheral vestibular disease. Abnormal signal processing within OP2 may underpin chronic dizziness following peripheral vestibular disease.
Blood bacterial DNA, intestinal adenoma and colorectal cancer
Authors: Mutignani Massimiliano , Penagini Roberto , Gargari Giorgio , Guglielmetti Simone , Cintolo Marcello , Airoldi Aldo , Leone Pierfrancesco , Carnevali Pietro , Ciafardini Clorinda , Petrocelli Giulio , Mascaretti Federica , Oreggia Barbara , Dioscoridi Lorenzo , Cavalcoli Federica , Primignani Massimo , Pugliese Francesco , Bertuccio Paola , Soru Pietro , Magistro Carmelo , Ferrari Giovanni , Speciani Michela , Bonato Giulia , Bini Marta , Cantù Paolo , Caprioli Flavio , Vangeli Marcello , Forti Edoardo , Mazza Stefano , Tosetti Giulia , Bonzi Rossella , Vecchi Maurizio , Vecchia Carlo La , Rossi Marta
Published: July 2021

Objective

We aimed to investigate the relation of blood bacterial DNA load and profiling with intestinal adenoma (IA) and colorectal cancer (CRC) patients.

Design

We performed 16S rRNA gene analysis of blood from 100 incident histologically confirmed CRC cases, 100 IA and 100 healthy subjects, matched to cases by centre, sex and age. Bacterial load was analysed using multiple conditional logistic regression. Differences in terms of abundance of bacteria between groups were estimated through analysis based on negative binomial distribution normalization. Random Forest was applied to predict the group assignment.

Results

We found an overrepresentation of blood 16S rRNA gene copies in colon cancer as compared to tumor-free controls (IA and healthy subjects). The odds ratio of colon cancer for the highest versus the lowest three quintiles of gene copies was 2.62. (95% confidence interval=1.22-5.65). No difference was found for rectal cancer and IA. For high 16S rRNA, community diversity was higher in colon cancers than controls. CRC cases had an enrichment of Peptostreptococcaceae and Acetobacteriaceae and a reduced abundance of Bacteroidaceae, Lachnospiraceae, and Ruminococcaceae. Identified variables predicted CRC from control and IA patients with an accuracy of 0.70.

Conclusion

Colon cancer patients had a higher DNA bacterial load and a different bacterial profiling as compared to healthy subjects, IA and rectal cancers, indicating a higher passage of bacteria from gastrointestinal tract to bloodstream. Further studies are needed to confirm this result and exploit it to conceive new non-invasive techniques for an early diagnosis of CRC.
Baseline psychological traits contribute to Lake Louise Acute Mountain Sickness score at high altitude
Authors: Talks Benjamin James , Campbell Catherine , Larcombe Stephanie J , Marlow Lucy , Finnegan Sarah L , Lewis Christopher T , Lucas Samuel J E , Harrison Olivia K , Pattinson Kyle TS
Published: July 2021

Background

Interoception refers to an individual’s ability to sense their internal bodily sensations. Acute mountain sickness (AMS) is a common feature of ascent to high altitude that is only partially explained by measures of peripheral physiology. We hypothesised that interoceptive ability may explain the disconnect between measures of physiology and symptom experience in AMS.

Methods and Material

Two groups of 18 participants were recruited to complete a respiratory interoceptive task three times at two-week intervals. The control group remained in Birmingham (140m altitude) for all three tests. The altitude group completed test 1 in Birmingham, test 2 the day after arrival at 2624m, and test 3 at 2728m after an 11-day trek at high altitude (up to 4800m).

Results

By measuring changes to metacognitive performance, we showed that acute ascent to altitude neither presented an interoceptive challenge, nor acted as interoceptive training. However, AMS symptom burden throughout the trek was found to relate to sea-level measures of anxiety, agoraphobia, and neuroticism.

Conclusions

This suggests that the Lake Louise AMS score is not solely a reflection of physiological changes on ascent to high altitude, despite often being used as such by researchers and commercial trekking companies alike.
Dissection of brain-wide spontaneous and functional somatosensory circuits by fMRI with optogenetic silencing
Authors: Jung Won Beom , Jiang Haiyan , Lee Soohyun , Kim Seong-Gi
Published: July 2021

To further advance functional magnetic resonance imaging (fMRI)-based brain science, it is critical to dissect fMRI activity at the circuit level. To achieve this goal, we combined brain-wide fMRI with neuronal silencing in well-defined regions. Since focal inactivation suppresses excitatory output to downstream pathways, intact input and suppressed output circuits can be separated. Highly specific cerebral blood volume-weighted fMRI was performed with optogenetic simulation of local GABAergic neurons in mouse somatosensory regions. Brain-wide spontaneous somatosensory networks were found mostly in ipsilateral cortical and subcortical areas, which differed from the bilateral homotopic connections commonly observed in resting-state fMRI data. The evoked fMRI responses to somatosensory stimulation in regions of the somatosensory network were successfully dissected, allowing the relative contributions of spinothalamic (ST), thalamocortical (TC), corticothalamic (CT), corticocortical (CC) inputs and local intracortical circuits to be determined. The ventral posterior thalamic nucleus (VPL) receives ST inputs, while the posterior medial thalamic nucleus (POm) receives CT inputs from the primary somatosensory cortex (S1) with TC inputs. The secondary somatosensory cortex (S2) receives mostly direct CC inputs from S1 and a few TC inputs from the VPL. The TC and CC input layers in cortical regions were identified by laminar-specific fMRI responses with a full width at half-maximum of <150 µm. Long-range synaptic inputs in cortical areas were amplified approximately 2-fold by local intracortical circuits, which is consistent with electrophysiological recordings. Overall, whole-brain fMRI with optogenetic inactivation revealed brain-wide, population-based long-range circuits, which could complement data typically collected in conventional microscopic functional circuit studies.
High-throughput production of functional prototissues capable of producing NO for vasodilation
Authors: Zhang Xiangxiang , Li Chao , Liu Fukai , Mu Wei , Ren Yongshuo , Yang Boyu , Han Xiaojun
Published: July 2021

Bottom-up synthesis of prototissues helps us to understand the internal cellular communications in the natural tissues and their functions, as well as to improve or repair the damaged tissues. The existed prototissues are rarely used to improve the function of living tissues. We demonstrated a methodology to produce spatially programmable prototissues based on the magneto-Archimedes effect in a high-throughput manner. More than 2000 prototissues are produced once within 2 hours. Two-component and three-component spatial coded prototissues are fabricated by varying the addition giant unilamellar vesicles (GUVs) order/number, and the magnetic field distributions. Two-step and three-step signal communications in the prototissues are realized using cascade enzyme reactions. More importantly, the two-component prototissues capable of producing nitric oxide (NO) cause vasodilation of rat blood vessels in the presence of glucose and hydroxyurea. The tension force decreases 2.59 g, meanwhile the blood vessel relaxation is of 31.2%. Our works pave the path to fabricate complicated programmable prototissues, and hold great potential in tissue transplantation in the biomedical field.
Acetyl-CoA metabolism drives epigenome change and contributes to carcinogenesis risk in fatty liver disease
Authors: Assante Gabriella , Chandrasekaran Sriram , Ng Stanley , Tourna Aikaterini , Chung Carolina H. , Isse Kowsar A. , Filippi Celine , Dhawan Anil , Liu Mo , Rozen Steven G. , Hoare Matthew , Campbell Peter , Ballard J. William. O. , Turner Nigel , Morris Margaret J. , Chokshi Shilpa , Youngson Neil A
Published: July 2021

The rate of nonalcoholic fatty liver disease (NAFLD)-associated hepatocellular carcinoma (HCC) is increasing worldwide, but the steps in precancerous hepatocytes which lead to HCC driver mutations are not well understood. Here we provide evidence that metabolically-driven histone hyperacetylation in steatotic hepatocytes can increase DNA damage to initiate carcinogenesis. Genome-wide histone acetylation is increased in steatotic livers of rodents fed high fructose or high fat diet. In vitro, steatosis relaxes chromatin and increases DNA damage marker γH2AX, which is reversed by inhibiting acetyl-CoA production. Steatosis-associated acetylation and γH2AX are enriched at gene clusters in telomere-proximal regions which contain HCC tumor suppressors in hepatocytes and human fatty livers. Regions of metabolically-driven epigenetic change also have increased levels of DNA mutation in non-cancerous tissue from NAFLD patients. Finally, genome-scale network modelling indicates that redox balance is a key contributor to this mechanism. Thus abnormal histone hyperacetylation is a potential initiating event in HCC carcinogenesis.
A competitive advantage through fast dead matter elimination in confined cellular aggregates
Authors: Pollack Yoav G. , Bittihn Philip , Golestanian Ramin
Published: July 2021

Competition of different species or cell types for limited space is relevant in a variety of biological processes such as biofilm development, tissue morphogenesis and tumor growth. Predicting the outcome for non-adversarial competition of such growing active matter is non-trivial, as it depends on how processes like growth, proliferation and the degradation of cellular matter are regulated in confinement; regulation that happens even in the absence of competition to achieve the dynamic steady state known as homeostasis. Here, we show that passive by-products of the processes maintaining homeostasis can significantly alter fitness. Even for purely pressure-regulated growth and exclusively mechanical interactions, this enables cell types with lower homeostatic pressure to outcompete those with higher homeostatic pressure. We reveal that interfaces play a critical role in the competition: There, growing matter with a higher proportion of active cells can better exploit local growth opportunities that continuously arise as the active processes keep the system out of mechanical equilibrium. We elucidate this effect in a theoretical toy model and test it in an agent-based computational model that includes finite-time mechanical persistence of dead cells and thereby decouples the density of growing cells from the homeostatic pressure. Our results suggest that self-organization of cellular aggregates into active and passive matter can be decisive for competition outcomes and that optimizing the proportion of growing (active) cells can be as important to survival as sensitivity to mechanical cues.
Assessing anatomical changes in male reproductive organs in response to larval crowding using micro-computed tomography imaging
Authors: Morimoto Juliano , Barcellos Renan , Schoborg Todd A. , Nogueira Liebert Parreiras , Colaço Marcos Vinicius
Published: July 2021

Ecological conditions shape (adaptive) responses at the molecular, anatomical, and behavioural levels. Understanding these responses is key to predict the outcomes of intra- and inter-specific competitions and the evolutionary trajectory of populations. Recent technological advances have enabled large-scale molecular (e.g., RNAseq) and behavioural (e.g., computer vision) studies, but the study of anatomical responses to ecological conditions has lagged behind. Here, we highlight the role of X-Ray micro-computed tomography (micro-CT) in generatingin vivoandex vivo3D imaging of anatomical structures, which can enable insights into adaptive anatomical responses to ecological environments. To demonstrate the application of this method, we manipulated the larval density ofDrosophila melanogasterflies and applied micro-CT to investigate the anatomical responses of the male reproductive organs to varying intra-specific competition levels during development. Our data is suggestive of two classes of anatomical responses which broadly agree with sexual selection theory: increasing larval density led to testes and ejaculatory duct to be overall larger (in volume), while the volume of accessory glands and, to a lesser extent, ejaculatory duct decreased. These two distinct classes of anatomical responses might reflect shared developmental regulation of the structures of the male reproductive system. Overall, we show that micro-CT can be an important tool to advance the study of anatomical (adaptive) responses to ecological environments.
Beneficial effects of novel strains of Aureobasidium pullulans produced 1,3-1,6 β-glucans on non-esterified fatty acid levels in diabetic KKAy mice
Authors: Ikewaki Nobunao , Onaka Takashi , Ikeue Yasunori , Nagataki Mitsuru , Kurosawa Gene , Dedeepiya Vidyasagar Devaprasad , Rajmohan Mathaiyan , Vaddi Suryaprakash , Senthilkumar Rajappa , Preethy Senthilkumar , Abraham Samuel JK
Published: July 2021

Obesity, metabolic syndrome, associated lipotoxicity and its cascade of events contribute to the majority of the burden related to non-communicable diseases globally. Preventive lifestyle changes aside, several beneficial effects have been reported in type II diabetes mellitus and dyslipidaemia patients with biological response modifier glucans (BRMG) produced as an exopolysaccharide by Aureobasidium pullulans. In this study, we compared two strains (AFO-202 and N-163) that produce beta glucans in alleviating lipotoxicity. This study was performed in obese diabetic mice model of KK-Ay mice, in four groups with six subjects in each group - Group 1: sacrificed on Day 0 for baseline values; Group 2: control (drinking water); Group 3: AFO-202 beta glucan—200 mg/kg/day; Group 4: N-163 beta glucan—300 mg/kg/day. The animals in groups 2–4 had the test solutions administered by gavage once daily for 28 consecutive days. Biochemical analyses were conducted of blood glucose, triglycerides, total cholesterol, LDL cholesterol, HDL cholesterol and non-esterified fatty acids (NEFA). Group 4 (N-163) had the lowest NEFA levels, as compared to the other groups, and marginally decreased triglyceride levels. The groups had no significant differences in blood glucose, HbA1c, triglycerides, or LDL and HDL cholesterol. N-163 produced by A. pullulans decreased NEFA in a diabetic mice model in 28 days. These results, although modest, warrant further in-depth research into lipotoxicity and associated inflammatory cascades in both healthy and disease affected subjects to develop novel strategies for prevention and management.
Effects of reward history on decision-making and movement vigor
Authors: Sukumar Shruthi , Shadmehr Reza , Ahmed Alaa A.
Published: July 2021

During foraging, animals explore a site and harvest reward, and then abandon that site and travel to the next opportunity. One aspect of this behavior involves decision-making, while the other involves movement control. We recently proposed that control of decision-making and movements may be linked via a desire to maximize a single normative utility: the sum of all rewards acquired, minus all efforts expended, divided by time. If this is the case, then the history of rewards, and not just its immediate availability, should dictate how long one decides to stay and harvest reward, and how fast one travels to the next opportunity. We tested this theory in a series of experiments in which humans used their hand to harvest tokens at a reward patch, and then used their arm to reach toward a subsequent opportunity. Experiencing a history of poor rewards not only led people to forage longer, but they also reached slower toward the next reward site. Thus, reward history had a consistent effect on both the decision-making process regarding when to abandon a reward site, and the motor control process regarding how fast to move to the next opportunity.
Metabolism is a major driver of hydrogen isotope fractionation recorded in tree-ring glucose of Pinus nigra
Authors: Wieloch Thomas , Grabner Michael , Augusti Angela , Serk Henrik , Ehlers Ina , Yu Jun , Schleucher Jürgen
Published: July 2021

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Stable isotope abundances convey valuable information about plant physiological processes and underlying environmental controls. Central gaps in our mechanistic understanding of hydrogen isotope abundances impede their widespread application within the plant and biogeosciences.

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To address these gaps, we analysed intramolecular deuterium abundances in glucose of Pinus nigra extracted from an annually resolved tree-ring series (1961 to 1995).

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We found fractionation signals (i.e., temporal variability in deuterium abundance) at glucose H1 and H2 introduced by closely related metabolic processes. Regression analysis indicates that these signals (and thus metabolism) respond to drought and atmospheric CO2 concentration beyond a response change point. They explain ≈60% of the whole-molecule deuterium variability. Altered metabolism is associated with below-average yet not exceptionally low growth.

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We propose the signals are introduced at the leaf-level by changes in sucrose-to-starch carbon partitioning and anaplerotic carbon flux into the Calvin-Benson cycle. In conclusion, metabolism can be the main driver of hydrogen isotope variation in plant glucose.
A burst of regulatory and protein innovation at the origin of placental mammals drove the emergence of placenta and underpins divergent early pregnancy strategies in modern mammals
Authors: Taylor Alysha S. , Tinning Haidee , Ovchinnikov Vladimir , Smith William , Pullinger Anna L. , Sutton Ruth A. , Constantinides Bede , Wang Dapeng , Forde Niamh , O’Connell Mary J
Published: July 2021

Summary paragraph

The origin of live birth in mammals ∼148 million years ago was a dramatic shift in reproductive strategy, yet the molecular changes that established mammal viviparity are largely unknown. Although progesterone receptor signalling predates the origin of mammals andis highly conserved in, and critical for, successful mammal pregnancy, it alone cannot explain the origin and subsequent diversity of implantation strategies throughout the placental mammal radiation. MiRNAs are known to be flexible and dynamic regulators with a well established role in the pathophysiology of mammal placenta. We propose that a dynamic core microRNA (miRNA) network originated early in placental mammal evolution, responds to conserved mammal pregnancy cues (e.g. progesterone), and facilitates species-specific responses. Here we identify 13 miRNAs that arose at the origin of placental mammals and were subsequently retained in all descendent lineages. The expression of these 13 miRNAs in response to early pregnancy molecules is regulated in a species-specific manner in endometrial epithelia of species with extremes of implantation strategies. Furthermore, these 13 miRNAs preferentially target 84 proteins under positive selective pressure on ancestral eutherian. Discovery of this core “live-birth” toolkit and specifically adapted proteins helps explain the origin and evolution of the placenta in mammals.
How clustered protocadherin binding specificity is tuned for neuronal self/non-self-recognition
Authors: Goodman Kerry M. , Katsamba Phinikoula S. , Rubinstein Rotem , Ahlsén Göran , Bahna Fabiana , Mannepalli Seetha , Dan Hanbin , Sampogna Rosemary , Shapiro Lawrence , Honig Barry
Published: July 2021

The stochastic expression of fewer than 60 clustered protocadherin (cPcdh) isoforms provides diverse identities to individual vertebrate neurons and a molecular basis for self/non-self- discrimination. cPcdhs form chains mediated by alternating cis and trans interactions between apposed membranes, which has been suggested to signal self-recognition. Such a mechanism requires that cPcdh cis dimers form promiscuously to generate diverse recognition units, and that trans interactions have precise specificity so that isoform mismatches terminate chain growth. However, the extent to which cPcdh interactions fulfill these requirements has not been definitively demonstrated. Here we report biophysical experiments showing that cPcdh cis interactions are promiscuous, but with preferences favoring formation of heterologous cis dimers. Trans-homophilic interactions are remarkably precise, with no evidence for heterophilic interactions between different isoforms. A new C-type cPcdh crystal structure and mutagenesis data help to explain these observations. Overall, the interaction characteristics we report for cPcdhs help explain their function in neuronal self/non-self-discrimination.
Large-scale characterization of cocaine addiction-like behaviors reveals that escalation of intake, aversion-resistant responding, and breaking-points are highly correlated measures of the same construct
Authors: de Guglielmo Giordano , Carrette Lieselot LG , Kallupi Marsida , Brennan Molly , Boomhower Brent , Maturin Lisa , Conlisk Dana , Sedighim Sharona , Tieu Lani , Fannon McKenzie J , Martinez Angelica R. , Velarde Nathan , Othman Dyar , Sichel Ben , Ramborger Jarryd , Lau Justin , Kononoff Jenni , Kimbrough Adam , Simpson Sierra , Smith Lauren C , Shankar Kokila , Bonnet-Zahedi Selene , Sneddon Elizabeth A. , Avelar Alicia , Plasil Sonja L. , Mosquera Joseph , Crook Caitlin , Chun Lucas , Vang Ashley , Milan Kristel K. , Schweitzer Paul , Lin Bonnie , Peng Beverly , Chitre Apurva , Polleskaya Oksana , Solberg Woods Leah C , Palmer Abraham A. , George Olivier
Published: July 2021

Addiction is commonly characterized by escalation of drug intake, compulsive drug seeking, and continued use despite harmful consequences. However, the factors contributing to the transition from moderate drug use to these problematic patterns remain unclear, particularly regarding the role of sex. Many preclinical studies have been limited by small sample sizes, low genetic diversity, and restricted drug access, making it challenging to model significant levels of intoxication or dependence and translate findings to humans. To address these limitations, we characterized addiction-like behaviors in a large sample of >500 outbred heterogeneous stock (HS) rats using an extended cocaine self-administration paradigm (6 h/daily). We analyzed individual differences in escalation of intake, progressive-ratio (PR) responding, continued use despite adverse consequences (contingent foot shocks), and irritability-like behavior during withdrawal. Principal component analysis showed that escalation of intake, progressive ratio responding, and continued use despite adverse consequences loaded onto a single factor that was distinct from irritability-like behaviors. Categorizing rats into resilient, mild, moderate, and severe addiction-like phenotypes showed that females exhibited higher addiction-like behaviors, with a lower proportion of resilient individuals compared to males. These findings suggest that, in genetically diverse rats with extended drug access, escalation of intake, continued use despite adverse consequences, and PR responding are highly correlated measures of a shared underlying construct. Furthermore, our results highlight sex differences in resilience to addiction-like behaviors.
THESEUS1 modulates cell wall stiffness and abscisic acid production in Arabidopsis thaliana
Authors: Bacete Laura , Schulz Julia , Engelsdorf Timo , Bartosova Zdenka , Vaahtera Lauri , Yan Guqi , Gerhold Joachim , Tichá Tereza , Øvstebø Camilla , Gigli-Bisceglia Nora , Johannessen-Starheim Svanhild , Margueritat Jeremie , Kollist Hannes , Dehoux Thomas , McAdam Scott A.M. , Hamann Thorsten
Published: July 2021

Plant cells can be distinguished from animal cells by their cell walls and high turgor pressure. Although changes in turgor and stiffness of cell walls seem coordinated, we know little about the mechanism responsible for coordination. Evidence has accumulated that plants, like yeast, have a dedicated cell wall integrity maintenance mechanism. This mechanism monitors the functional integrity of the wall and maintains it through adaptive responses when cell wall damage occurs during growth, development, and interactions with the environment. The adaptive responses include osmo-sensitive-induction of phytohormone production, defence responses as well as changes in cell wall composition and structure. Here, we investigate how the cell wall integrity maintenance mechanism coordinates changes in cell wall stiffness and turgor in Arabidopsis thaliana. We show that the production of abscisic acid (ABA), the phytohormone modulating turgor pressure and responses to drought, depends on the presence of a functional cell wall. We find that the cell wall integrity sensor THESEUS1 modulates mechanical properties of walls, turgor loss point and ABA biosynthesis. We identify RECEPTOR-LIKE PROTEIN 12 as a new component of cell wall integrity maintenance controlling cell wall damage-induced jasmonic acid production. Based on the results we propose that THE1 is responsible for coordinating changes in turgor pressure and cell wall stiffness.

Significance statement

Plants need to constantly adapt to a changing environment. This includes responses to biotic and abiotic stress. Key elements influencing the response to abiotic stress are the plant cell walls surrounding all cells and the phytohormone abscisic acid, which influences turgor pressure in plants. Turgor pressure in plant cells is much higher than in animal cells and a key driver of plant growth and development. Here we investigate the mechanism regulating cell wall stiffness and coordinating changes in stiffness and turgor. We characterize key elements of the mechanism and dissect its mode of action. This knowledge will enable us to pursue novel approaches to improve plant resistance to drought stress, which is crucial in a rapidly changing environment.
Polymer-Conjugated Carbon Nanotubes for Biomolecule Loading
Authors: Jackson Christopher T. , Wang Jeffrey W. , González-Grandío Eduardo , Goh Natalie S. , Mun Jaewan , Krishnan Sejal , Landry Markita P.
Published: July 2021

Nanomaterials have emerged as an invaluable tool for the delivery of biomolecules such as DNA and RNA, with various applications in genetic engineering and post-transcriptional genetic manipulation. Alongside this development, there has been an increasing use of polymer-based techniques, such as polyethyleneimine (PEI), to electrostatically load polynucleotide cargoes onto nanomaterial carriers. However, there remains a need to assess nanomaterial properties, conjugation conditions, and biocompatibility of these nanomaterial-polymer constructs, particularly for use in plant systems. In this work, we develop mechanisms to optimize DNA loading on single-walled carbon nanotubes (SWNTs) with a library of polymer-SWNT constructs and assess DNA loading ability, polydispersity, and both chemical and colloidal stability. Counterintuitively, we demonstrate that polymer hydrolysis from nanomaterial surfaces can occur depending on polymer properties and attachment chemistries, and describe mitigation strategies against construct degradation. Given the growing interest in delivery applications in plant systems, we also assess the toxicity of polymer-based nanomaterials in plants and provide recommendations for future design of nanomaterial-based polynucleotide delivery strategies.
Leptin protects against the development and expression of cocaine addiction-like behavior in heterogenous stock rats
Authors: Carrette L.L.G. , Coral C. , Crook C. , Boomhower B. , Brennan M. , Ortez C. , Shankar K. , Simpson S. , Maturin L. , de Guglielmo G. , Woods L. Solberg , Palmer A. A. , George O.
Published: July 2021

In addition to its pleasurable effects, weight control is a significant contributor to initiation, maintenance and relapse of cocaine use. This suggests that individual differences in bodyweight control and feeding hormones, such as leptin may contribute to the vulnerability to cocaine use disorder. While pre-clinical studies have shown a mutually inhibitory relationship between leptin and cocaine, they have used small sample sizes and did not investigate individual differences in a large heterogeneous population. Here, we tested if individual differences in bodyweight and blood leptin level is associated with high or low vulnerability to addiction-like behaviors using data from 500 heterogenous stock rats and 160 blood samples from the Cocaine Biobank, using a model of extended access to intravenous self-administration of cocaine. Finally, we tested a separate cohort to evaluate the causal effect of exogenous leptin administration on cocaine seeking. Bodyweight, while changing due to cocaine self-administration in males, was not related to the vulnerability to addiction-like behavior. Blood leptin levels after ~6 weeks of cocaine self-administration did not correlate with addiction-like behaviors, however, baseline blood leptin levels before any access to cocaine negatively predicted addiction-like behavior. Finally, administration of leptin reduced cocaine intake after acute withdrawal and cocaine seeking after 6 weeks of protracted abstinence. These results demonstrate that high blood leptin level before access to cocaine may be a protective factor against the development of cocaine addiction-like behavior, that exogenous leptin reduces the motivation to take and seek cocaine, but that blood leptin level and bodyweight changes in current users are not good biomarkers for addiction-like behaviors.
Exome first approach to reduce diagnostic costs and time – retrospective analysis of 111 individuals with rare neurodevelopmental disorders
Authors: Klau Julia , Jamra Rami Abou , Radtke Maximilian , Oppermann Henry , Lemke Johannes R. , Beblo Skadi , Popp Bernt
Published: July 2021

This single center study aims to determine the time, diagnostic procedure and cost saving potential of early exome sequencing in a cohort of 111 individuals with genetically confirmed neurodevelopmental disorders.

We retrospectively collected data regarding diagnostic time points and procedures from the individuals’ medical histories and developed criteria for classifying diagnostic procedures in terms of requirement, followed by a cost allocation. The genetic variants of all individuals were reevaluated according to ACMG recommendations and considering the individuals’ phenotype.

Individuals who developed first symptoms of their underlying genetic disorder when Next Generation Sequencing (NGS) diagnostics were already available received a diagnosis significantly faster than individuals with first symptoms before this cutoff. The largest amount of potentially dispensable diagnostics was found in genetic, metabolic, and cranial magnetic resonance imaging examinations. Out of 407 performed genetic examinations, 296 (72.7%) were classified as potentially dispensable. The same applied to 36 (27.9%) of 129 cranial magnetic resonance imaging and 111 (31.8%) of 349 metabolic examinations. Dispensable genetic examinations accounted 302,947.07€ (90.2%) of the total 335,837.49€ in potentially savable costs in this cohort. The remaining 32,890.42€ (9.8%) are related to non-required metabolic and cranial magnetic resonance imaging diagnostics. On average, the total potentially savable costs in our study amount to €3,025.56 per individual.

Cost savings by first tier exome sequencing lie primarily in genetic, metabolic, and cMRI testing in this German cohort, underscoring the utility of performing exome sequencing at the beginning of the diagnostic pathway and the potential for saving diagnostic costs and time.
Controlled human malaria infection with PvW1 – a new clone of Plasmodium vivax with high quality genome assembly
Authors: Minassian Angela M. , Themistocleous Yrene , Silk Sarah E. , Barrett Jordan R. , Kemp Alison , Quinkert Doris , Nielsen Carolyn M. , Edwards Nick J. , Rawlinson Thomas A. , Lopez Fernando Ramos , Roobsoong Wanlapa , Ellis Katherine J. , Cho Jee-Sun , Aunin Eerik , Otto Thomas D. , Reid Adam J. , Bach Florian , Labbé Geneviève M. , Poulton Ian D. , Marini Arianna , Zaric Marija , Mulatier Margaux , Ramon Raquel Lopez , Baker Megan , Mitton Celia H. , Sousa Jason C. , Rachaphaew Nattawan , Kumpitak Chalermpon , Maneechai Nongnuj , Suansomjit Chayanut , Piteekan Tianrat , Hou Mimi M. , Khozoee Baktash , Roberts David J. , Lawrie Alison M. , Blagborough Andrew M. , Nugent Fay L. , Taylor Iona J. , Johnson Kimberly J. , Spence Philip J. , Sattabongkot Jetsumon , Biswas Sumi , Rayner Julian C. , Draper Simon J.
Published: July 2021

Controlled human malaria infection (CHMI) provides a highly informative means to investigate host-pathogen interactions and enable in vivo proof-of-concept efficacy testing of new drugs and vaccines. However, unlike Plasmodium falciparum, well-characterized P. vivax parasites that are safe and suitable for use in modern CHMI models are limited. Here, two healthy malaria-naïve UK adults with universal donor blood group were safely infected with a clone of P. vivax from Thailand by mosquito-bite CHMI. Parasitemia developed in both volunteers and, prior to treatment, each volunteer donated blood to produce a cryopreserved stabilate of infected red blood cells. Following stringent safety screening, the parasite stabilate from one of these donors (“PvW1”) was thawed and used to inoculate six healthy malaria-naïve UK adults by blood-stage CHMI, at three different dilutions. Parasitemia developed in all volunteers, who were then successfully drug treated. PvW1 parasite DNA was isolated and sequenced to produce a high quality genome assembly by using a hybrid assembly method. We analysed leading vaccine candidate antigens and multigene families, including the Vivax interspersed repeat (VIR) genes of which we identified 1145 in the PvW1 genome. Our genomic analysis will guide future assessment of candidate vaccines and drugs, as well as experimental medicine studies.
Understanding the role of memory re-activation and cross-reactivity in the defense against SARS-CoV-2
Authors: Denninger Viola , Xu Catherine K. , Meisl Georg , Morgunov Alexey S. , Fiedler Sebastian , Ilsley Alison , Emmenegger Marc , Malik Anisa Y. , Piziorska Monika A. , Schneider Matthias M. , Devenish Sean R. A. , Kosmoliaptsis Vasilis , Aguzzi Adriano , Fiegler Heike , Knowles Tuomas P. J.
Published: July 2021

Recent efforts in understanding the course and severity of SARS-CoV-2 infections have highlighted both potential beneficial as well as detrimental effects of cross-reactive antibodies derived from memory immunity. Specifically, due to a significant degree of sequence similarity between SARS-CoV-2 and other members of the coronavirus family, memory B-cells that emerged from previous infections with endemic human coronaviruses (HCoVs) could be re-activated upon encountering the newly emerged SARS-CoV-2, thus prompting the production of cross-reactive antibodies. Understanding the affinity and concentration of these potentially cross-reactive antibodies to the new SARS-CoV-2 antigens is therefore particularly important when assessing both existing immunity against common HCoVs and adverse effects like antibody-dependent enhancement (ADE) in COVID-19. However, these two fundamental parameters cannot easily be deconvoluted by surface-based assays like enzyme-linked immunosorbent assays (ELISAs) which are routinely used to assess cross-reactivity.

Here, we have used microfluidic antibody-affinity profiling (MAAP) to quantitatively evaluate the humoral immune response in COVID-19 convalescent patients by determining both antibody affinity and concentration against spike antigens of SARS-CoV-2 directly in nine convalescent COVID-19 patient and three pre-pandemic sera that were seropositive for common HCoVs. All 12 sera contained low concentrations of high affinity antibodies against spike antigens of HCoV-NL63 and HCoV-HKU1, indicative of past exposure to these pathogens, while the affinity against the SARS-CoV-2 spike protein was lower. These results suggest that cross-reactivity as a consequence of memory re-activation upon an acute SARS-CoV-2 infection may not be a significant factor in generating immunity against SARS-CoV-2.
Maternal gut microbiota Bifidobacterium promotes placental morphogenesis, nutrient transport and fetal growth in mice
Authors: Lopez-Tello Jorge , Schofield Zoe , Kiu Raymond , Dalby Matthew J. , van Sinderen Douwe , Le Gall Gwénaëlle , Sferruzzi-Perri Amanda N , Hall Lindsay J
Published: July 2021

The gut microbiota plays a central role in regulating host metabolism. While substantial progress has been made in discerning how the microbiota influences host functions post birth and beyond, little is known about how key members of the maternal gut microbiota can influence feto-placental growth. Notably, in pregnant women, Bifidobacterium represents a key beneficial microbiota genus, with levels observed to increase across pregnancy. Here, using germ-free and specific-pathogen-free mice, we demonstrate that the bacterium Bifidobacterium breve UCC2003 modulates maternal body adaptations, placental structure and nutrient transporter capacity, with implications for fetal metabolism and growth. Maternal and placental metabolome were affected by maternal gut microbiota (i.e. acetate, formate and carnitine). Histological analysis of the placenta confirmed that Bifidobacterium modifies placental structure via changes in Igf2P0, Dlk1, Mapk1 and Mapk14 expression. Additionally, B. breve UCC2003, acting through Slc2a1 and Fatp1-4 transporters, was shown to restore fetal glycaemia and fetal growth in association with changes in the fetal hepatic transcriptome. Our work emphasizes the importance of the maternal gut microbiota on feto-placental development and sets a foundation for future research towards the use of probiotics during pregnancy.
PDZ-containing proteins targeted by the ACE2 receptor
Authors: Caillet-Saguy Célia , Wolff Nicolas
Published: July 2021

Angiotensin converting enzyme 2 (ACE2) is a main receptor for SARS-CoV-2 entry to the host cell. Indeed, the first step in viral entry is the binding of the viral trimeric spike protein to ACE2. Abundantly present in human epithelial cells of many organs, ACE2 is also expressed in the human brain. ACE2 is a type I membrane protein with an extracellular N-terminal peptidase domain and a C-terminal collectrin-like domain that ends with a single transmembrane helix and an intracellular 44-residues segment. This C-terminal segment contains a PDZ-binding motif (PBM) targeting protein interacting domains called PSD-95/Dlg/ZO-1 (PDZ).

Here, we identified the human PDZ specificity profile of the ACE2 PBM using the high throughput holdup assay and measuring the binding intensities of the PBM of ACE2 against the full human PDZome. We discovered 14 human PDZ binders of ACE2 showing significant binding with dissociation constants values ranging from 3 to 81 μM. NHERF, SHANK, and SNX27 proteins found in this study are involved in protein trafficking. The PDZ/PBM interactions with ACE2 could play a role on ACE2 internalization and recycling that could benefit for the virus entry. Interestingly, most of the ACE2 partners we identified are expressed in neuronal cells, such as SHANK and MAST families, and modifications of the interactions between ACE2 and these neuronal proteins may be involved in neurological symptoms of COVID-19.