bluuebunny/crossref_metadata_2025 huggingface dataset:
Treatment of Complex Desmoid Tumors in Familial Adenomatous Polyposis Syndrome by Intestinal Transplantation
Authors: Canovai Emilio , Butler Andrew , Clark Susan , Latchford Andrew , Sinha Ashish , Sharkey Lisa , Rutter Charlotte , Russell Neil , Upponi Sara , Amin Irum
Published: January 2024

Background.

Desmoid tumors are fibroblastic lesions which often have an unpredictable and variable clinical course. In the context of familial adenomatous polyposis (FAP), these frequently occur intra-abdominally, especially in the small-bowel mesentery resulting in sepsis, fistulation, and invasion of the abdominal wall and retroperitoneum. In selected cases where other modalities have failed, the most radical option is to perform a total enterectomy and intestinal transplantation (ITx). In this study, we present our center’s experience of ITx for desmoid in patients with FAP.

Methods.

We performed a retrospective review of our prospectively collected database between 2007 and 2022. All patients undergoing ITx for FAP-related desmoid were included.

Results.

Between October 2007 and September 2023, 144 ITx were performed on 130 patients at our center. Of these, 15 patients (9%) were for desmoid associated with FAP (7 modified multivisceral transplants, 6 isolated ITx, and 2 liver-containing grafts). The median follow-up was 57 mo (8–119); 5-y patient survival was 82%, all with functioning grafts without local desmoid recurrence. These patients presented us with several complex surgical issues, such as loss of abdominal domain, retroperitoneal/abdominal wall involvement, ileoanal pouch–related issues, and the need for foregut resection because of adenomatous disease.

Conclusions.

ITx is a viable treatment in selected patients with FAP and extensive desmoid disease. The decision to refer for ITx can be challenging, particularly the timing and sequence of treatment (simultaneous versus sequential exenteration). Delays can result in additional disease burden, such as secondary liver disease or invasion of adjacent structures.
Cross-societal variation in norm enforcement systems
Authors: Molho Catherine , De Petrillo Francesca , Garfield Zachary H. , Slewe Sam
Published: January 2024

Across human societies, people are sometimes willing to punish norm violators. Such punishment can take the form of revenge from victims, seemingly altruistic intervention from third parties, or legitimized sanctioning from institutional representatives. Although prior work has documented cross-cultural regularities in norm enforcement, substantial variation exists in the prevalence and forms of punishment across societies. Such cross-societal variation may arise from universal psychological mechanisms responding to different socio-ecological conditions, or from cultural evolutionary processes, resulting in different norm enforcement systems. To date, empirical evidence from comparative studies across diverse societies has remained disconnected, owing to a lack of interdisciplinary integration and a prevalent tendency of empirical studies to focus on different underpinnings of variation in norm enforcement. To provide a more complete view of the shared and unique aspects of punishment across societies, we review prior research in anthropology, economics and psychology, and take a first step towards integrating the plethora of socio-ecological and cultural factors proposed to explain cross-societal variation in norm enforcement. We conclude by discussing how future cross-societal research can use diverse methodologies to illuminate key questions on the domain-specificity of punishment, the diversity of tactics supporting social norms, and their role in processes of norm change.

This article is part of the theme issue ‘Social norm change: drivers and consequences’.
The expressive function of public policy: renewable energy mandates signal social norms
Authors: Syropoulos Stylianos , Sparkman Gregg , Constantino Sara M.
Published: January 2024

Addressing collective action problems requires individuals to engage in coordinated and cooperative behaviours. Existing research suggests that individuals' propensity to work together depends in part on their belief that others support the cause in question. People form their expectations about prevalent beliefs and behaviours from many sources. To date, most of the literature has focussed on how social norm perceptions are inferred from peers or summary statistics. We explore an understudied source of norm information: the passage of policies by democratically elected institutions. Institutional signals, such as the setting of defaults, national laws or policies, can act as coordination devices, signalling or prescribing social norms to large audiences. However, their expressive function is likely to depend on whether the institution is seen as accountable to the public. In two highly powered, pre-registered experiments (N= 11 636), we examine the role of policy signals as a source of social norm information. In Study 1, Americans randomly assigned to learn that their state passed a 100% renewable energy mandate believe that a greater percentage of their state's residents support such a mandate. In Study 2, we replicate this effect for national policy and show that the influence is moderated by information about whether the government represents the will of the people.

This article is part of the theme issue ‘Social norm change: drivers and consequences’.
miR-100andmiR-125bContribute to Enhanced 3D Growth and Invasiveness and can be Functionally Transferred to Silence Target Genes in Recipient Cells
Authors: Nelson Hannah M. , Qu Shimian , Huang Liyu , Shameer Muhammad , Corn Kevin C. , Chapman Sydney N. , Luthcke Nicole L. , Schuster Sara A. , Turnbull Lauren A. , Guy Lucas L. , Liu Xiao , Vickers Kasey C. , Liu Qi , Franklin Jeffrey L. , Weaver Alissa M. , Rafat Marjan , Coffey Robert J. , Patton James G.
Published: January 2024

Extracellular communication via the transfer of vesicles and nanoparticles is now recognized to play an important role in tumor microenvironment interactions. Cancer cells upregulate and secrete abundant levels ofmiR-100andmiR-125bthat can alter gene expression by both cell- and non-cell-autonomous mechanisms. We previously showed that these miRNAs activate Wnt signaling in colorectal cancer (CRC) through noncanonical pairing with 5 negative regulators of Wnt signaling. To identify additional targets ofmiR-100andmiR-125b, we used bioinformatic approaches comparing multiple CRC cell lines, including knockout lines lacking one or both of these miRNAs. From an initial list of 96 potential mRNA targets, we tested 15 targets with 8 showing significant downregulation in the presence ofmiR-100andmiR-125b. Among these, Cingulin (CGN) and Protein tyrosine phosphatase receptor type-R (PTPRR) are downregulated in multiple cancers, consistent with regulation by increased levels ofmiR-100andmiR-125b.We also show that increased cellular levels ofmiR-100andmiR-125benhance 3D growth and invasiveness in CRC and glioblastoma cell lines. Lastly, we demonstrate that extracellular transfer ofmiR-100andmiR-125bcan silence both reporter and endogenous mRNA targets in recipient cells and also increase the invasiveness of recipient spheroid colonies when grown under 3D conditions in type I collagen.
Copper drives remodeling of metabolic state and progression of clear cell renal cell carcinoma
Authors: Bischoff Megan E. , Shamsaei Behrouz , Yang Juechen , Secic Dina , Vemuri Bhargav , Reisz Julie A. , D’Alessandro Angelo , Bartolacci Caterina , Adamczak Rafal , Schmidt Lucas , Wang Jiang , Martines Amelia , Biesiada Jacek , Vest Katherine E. , Scaglioni Pier P. , Plas David R. , Patra Krushna C. , Gulati Shuchi , Figueroa Julio A. Landero , Meller Jarek , Cunningham J. Tom , Czyzyk-Krzeska Maria F.
Published: January 2024

Copper (Cu) is an essential trace element required for mitochondrial respiration. Late-stage clear cell renal cell carcinoma (ccRCC) accumulates Cu and allocates it to mitochondrial cytochrome c oxidase. We show that Cu drives coordinated metabolic remodeling of bioenergy, biosynthesis and redox homeostasis, promoting tumor growth and progression of ccRCC. Specifically, Cu induces TCA cycle-dependent oxidation of glucose and its utilization for glutathione biosynthesis to protect against H2O2generated during mitochondrial respiration, therefore coordinating bioenergy production with redox protection. scRNA-seq determined that ccRCC progression involves increased expression of subunits of respiratory complexes, genes in glutathione and Cu metabolism, and NRF2 targets, alongside a decrease in HIF activity, a hallmark of ccRCC. Spatial transcriptomics identified that proliferating cancer cells are embedded in clusters of cells with oxidative metabolism supporting effects of metabolic states on ccRCC progression. Our work establishes novel vulnerabilities with potential for therapeutic interventions in ccRCC.

Accumulation of copper is associated with progression and relapse of ccRCC and drives tumor growth.

Cu accumulation and allocation to cytochrome c oxidase (CuCOX) remodels metabolism coupling energy production and nucleotide biosynthesis with maintenance of redox homeostasis.

Cu induces oxidative phosphorylation via alterations in the mitochondrial proteome and lipidome necessary for the formation of the respiratory supercomplexes.

Cu stimulates glutathione biosynthesis and glutathione derived specifically from glucose is necessary for survival of CuHicells. Biosynthesis of glucose-derived glutathione requires activity of glutamyl pyruvate transaminase 2, entry of glucose-derived pyruvate to mitochondria via alanine, and the glutamate exporter, SLC25A22. Glutathione derived from glucose maintains redox homeostasis in Cu-treated cells, reducing Cu-H2O2Fenton-like reaction mediated cell death.

Progression of human ccRCC is associated with gene expression signature characterized by induction of ETC/OxPhos/GSH/Cu-related genes and decrease in HIF/glycolytic genes in subpopulations of cancer cells. Enhanced, concordant expression of genes related to ETC/OxPhos, GSH, and Cu characterizes metabolically active subpopulations of ccRCC cells in regions adjacent to proliferative subpopulations of ccRCC cells, implicating oxidative metabolism in supporting tumor growth.
Negative allosteric modulation of CB1 cannabinoid receptor signaling decreases intravenous morphine self-administration and relapse in mice
Authors: Oliva Idaira , Kazi Fezaan , Cantwell Lucas N. , Thakur Ganesh A. , Crystal Jonathon D. , Hohmann Andrea G.
Published: January 2024

The endocannabinoid system interacts with the reward system to modulate responsiveness to natural reinforcers, as well as drugs of abuse. Previous preclinical studies suggested that direct blockade of CB1 cannabinoid receptors (CB1R) could be leveraged as a potential pharmacological approach to treat substance use disorder, but this strategy failed during clinical trials due to severe psychiatric side effects. Alternative strategies have emerged to circumvent the side effects of direct CB1 binding through the development of allosteric modulators. We hypothesized that pharmacological inhibition of CB1R signaling through negative allosteric modulation (NAM) would reduce the reinforcing properties of morphine and decrease opioid addictive behaviors. By employing i.v. self-administration in mice, we studied the effects of the CB1-biased NAM GAT358 on morphine intake, relapse-like behavior, and motivation to work for morphine infusions. Our data revealed that GAT358 reduced morphine infusion intake during the maintenance phase of morphine self-administration under fixed ratio 1 schedule of reinforcement. GAT358 decreased morphine-seeking behavior after forced abstinence. Moreover, GAT358 dose-dependently decreased the motivation to obtain morphine infusions in a progressive ratio schedule of reinforcement. Strikingly, GAT358 did not affect the motivation to work for food rewards in an identical progressive ratio task, suggesting that the effect of GAT358 in decreasing opioid self-administration is reward specific. Furthermore, GAT58 did not produce motor ataxia in the rota-rod test. Our results suggest that CB1R NAMs reduced the reinforcing properties of morphine and could represent a viable therapeutic route to safely decrease opioid-addicted behaviors.
Gut microbiome carbon and sulfur metabolisms supportSalmonelladuring pathogen infection
Authors: Leleiwi Ikaia , Kokkinias Katherine , Kim Yongseok , Baniasad Maryam , Shaffer Michael , Sabag-Daigle Anice , Daly Rebecca A. , Flynn Rory M. , Wysocki Vicki H. , Ahmer Brian M. M. , Borton Mikayla A. , Wrighton Kelly C.
Published: January 2024

Salmonella entericaserovar Typhimurium is a pervasive enteric pathogen and an ongoing global threat to public health. Ecological studies in theSalmonellaimpacted gut remain underrepresented in the literature, discounting the microbiome mediated interactions that may informSalmonellaphysiology during colonization and infection. To understand the microbial ecology ofSalmonellaremodeling of the gut microbiome, here we performed multi-omics approaches on fecal microbial communities from untreated andSalmonella-infected mice. Reconstructed genomes recruited metatranscriptomic and metabolomic data providing a strain-resolved view of the expressed metabolisms of the microbiome duringSalmonellainfection. This data informed possibleSalmonellainteractions with members of the gut microbiome that were previously uncharacterized.Salmonella-induced inflammation significantly reduced the diversity of transcriptionally active members in the gut microbiome, yet increased gene expression was detected for 7 members, withLuxibacterandLigilactobacillusbeing the most active. Metatranscriptomic insights fromSalmonellaand other persistent taxa in the inflamed microbiome further expounded the necessity for oxidative tolerance mechanisms to endure the host inflammatory responses to infection. In the inflamed gut lactate was a key metabolite, with microbiota production and consumption reported amongst transcriptionally active members. We also showed that organic sulfur sources could be converted by gut microbiota to yield inorganic sulfur pools that become oxidized in the inflamed gut, resulting in thiosulfate and tetrathionate that supportsSalmonellarespiration. Advancement of pathobiome understanding beyond inferences from prior amplicon-based approaches can hold promise for infection mitigation, with the active community outlined here offering intriguing organismal and metabolic therapeutic targets.
Efficacy of auxin-inducible protein degradation inC. eleganstissues using different auxins and TIR1-expressing strains
Authors: Sharma Nidhi , Marques Filipe , Kratsios Paschalis
Published: January 2024

The auxin-inducible degradation system has emerged as a powerful tool to deplete proteins of interest in cells and tissues of various model organisms, includingC. elegans2–5. Here, we present a detailed protocol to perform AID-driven spatiotemporal depletion of specific proteins inC. eleganstissues. First, we introduced the AID degron and a fluorescent reporter at two conserved proteins: (a) the transcription factor CFI-1 (human ARID3), which is expressed in the nucleus of multipleC. elegansneurons and head muscle cells6,7, and (b) the broadly expressed translation initiation factor Y47D3A.21 (human DENR) that localizes in the cytoplasm. Second, we provide a step-by-step guide on how to generateC. elegansstrains suitable for AID-mediated protein (CFI-1 and DENR) depletion. Third, we find that the degree of CFI-1 and DENR depletion inC. eleganstissues is comparable upon treatment with either natural auxin (indole-3-acetic acid (IAA) or a water-soluble synthetic auxin analog (K-NAA). Last, we compare the degree of AID-mediated CFI-1 depletion inC. elegansneurons when the transport inhibitor response 1 (TIR1), component of the SCF ubiquitin ligase complex, is provided in neurons or all somatic cells. Altogether, this protocol provides side-by-side comparisons of different auxins and TIR1-expressing lines. Such comparisons may benefit future studies of AID-mediated protein depletion inC. elegans.

Graphical abstract

Image provided as pdf (together with Figures).

Highlights

Efficient protein depletion inC. eleganstissues upon treatment with either natural or synthetic auxins.

Pansomatic TIR1 expression leads to efficient depletion of CFI-1 and DENR.

Panneuronal TIR1 expression leads to neuron-specific, yet variable CFI-1 depletion.

The AID system is compatible with fluorescence microscopy, Western blotting and behavioral assays.
Dietary tryptophan and genetic susceptibility expand gut microbiota that promote systemic autoimmune activation
Authors: Ma Longhuan , Ge Yong , Brown Josephine , Choi Seung-Chul , Elshikha Ahmed , Kanda Nathalie , Terrell Morgan , Six Natalie , Garcia Abigail , Mohamadzadeh Mansour , Silverman Gregg , Morel Laurence
Published: January 2024

Tryptophan modulates disease activity and the composition of microbiota in the B6.Sle1.Sle2.Sle3(TC) mouse model of lupus. To directly test the effect of tryptophan on the gut microbiome, we transplanted fecal samples from TC and B6 control mice into germ-free or antibiotic-treated non-autoimmune B6 mice that were fed with a high or low tryptophan diet. The recipient mice with TC microbiota and high tryptophan diet had higher levels of immune activation, autoantibody production and intestinal inflammation. A bloom ofRuminococcus gnavus (Rg),a bacterium associated with disease flares in lupus patients, only emerged in the recipients of TC microbiota fed with high tryptophan.Rgdepletion in TC mice decreased autoantibody production and increased the frequency of regulatory T cells. Conversely, TC mice colonized withRgshowed higher autoimmune activation. Overall, these results suggest that the interplay of genetic and tryptophan can influence the pathogenesis of lupus through the gut microbiota.
Injury Severity is a Key Contributor to Coagulation Dysregulation and Fibrinogen Consumption
Authors: Gosselin Andrew R. , Bargoud Christopher G. , Sawalkar Abhishek , Mathew Shane , Toussaint Ashley , Greenen Matthew , Coyle Susette M. , Macor Marie , Krishnan Anandi , Goswami Julie , Hanna Joseph S. , Tutwiler Valerie
Published: January 2024

Background

Traumatic injury is a leading cause of death for those under the age of 45, with 40% occurring due to hemorrhage. Severe tissue injury and hypoperfusion lead to marked changes in coagulation, thereby preventing formation of a stable blood clot and increasing hemorrhage associated mortality.

Objectives

We aimed to quantify changes in clot formation and mechanics occurring after traumatic injury and the relationship to coagulation kinetics, and fibrinolysis.

Methods

Plasma was isolated from injured patients upon arrival to the emergency department. Coagulation kinetics and mechanics of healthy donors and patient plasma were compared with rheological, turbidimetric and thrombin generation assays. ELISA’s were performed to determine tissue plasminogen activator (tPA) and D-dimer concentration, as fibrinolytic markers.

Results

Sixty-three patients were included in the study. The median injury severity score (ISS) was 17, median age was 37.5 years old, and mortality rate was 30%. Rheological, turbidimetric and thrombin generation assays indicated that trauma patients on average, and especially deceased patients, exhibited reduced clot stiffness, increased fibrinolysis and reduced thrombin generation compared to healthy donors. Fibrinogen concentration, clot stiffness, D-dimer and tPA all demonstrated significant direct correlation to increasing ISS. Machine learning algorithms identified and highlighted the importance of clinical factors on determining patient outcomes.

Conclusions

Viscoelastic and biochemical assays indicate significant contributors and predictors of mortality for improved patient treatment and therapeutic target detection.

ESSENTIALS

Traumatic injury may lead to alterations in a patient’s ability to form stable blood clots

A study was performed to assess how trauma severity affects coagulation kinetics

Key alterations were observed in trauma patients, who exhibit weaker and slower forming clots

Paired with machine learning methods, the results indicate key aspects contributing to mortality
Cardiovascular risk in ANCA-associated vasculitis: monocyte phenotyping reveals distinctive signatures between serological subsets
Authors: Vegting Yosta , Hanford Katie ML , Jongejan Aldo , Gajadin Gayle RS , Versloot Miranda , van der Bom-Baylon Nelly D , Dekker Tamara , Penne E Lars , van der Heijden Joost W , Houben Eline , Bemelman Frederike J , Neele Annette E , Moerland Perry D , Vogt Liffert , Kroon Jeffrey , Hilhorst Marc L
Published: January 2024

Objectives

Anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitides (AAV) is associated with an increased cardiovascular risk, particularly the myeloperoxidase AAV serotype (MPO-AAV). Distinct alterations in monocyte phenotypes may cause accelerated atherosclerotic disease in AAV.

Methods

A cohort including 43 AAV patients and 19 healthy controls were included for downstream analyses. Extensive phenotyping of monocytes and monocyte-derived macrophages was performed using bulk RNA-sequencing and flow cytometry. Anin vitrotransendothelial migration assay reflecting intrinsic adhesive and migratory capacities of monocytes was employed. Subsequent sub-analyses were performed to investigate differences between serological subtypes.

Results

Monocyte subset analysis showed increased classical monocytes during active disease, whereas non-classical monocytes were decreased. RNA-sequencing revealed upregulation of distinct inflammatory pathways and lipid metabolism-related markers in monocytes of active AAV patients. No differences were detected in the intrinsic monocyte adhesion and migration capacity. Monocytes of MPO-AAV patients in remission expressed genes related to inflammation, coagulation, platelet-binding and interferon signalling, whereas the expression of chemokine receptors indicative of acute inflammation and monocyte extravasation (i.e., CCR2 and CCR5) was increased in monocytes of proteinase-3(PR3)-AAV patients. During active disease, PR3-AAV was linked with elevated serum CRP and increased platelet counts compared to MPO-AAV.

Conclusion

These findings highlight changes in monocyte subset composition and activation, but not in the intrinsic migration capacity of AAV monocytes. MPO-AAV monocytes are associated with sustained upregulation of inflammatory genes, whereas PR3-AAV monocytes exhibit chemokine receptor upregulation. These molecular changes may play a role in elevating cardiovascular risk as well as in the underlying pathophysiology of AAV.

Key messages

- Monocytes are activated during active ANCA-associated vasculitis (AAV) and upregulate lipid metabolism-related markers

- AAV monocytes have a normal intrinsic adhesion and migration capacity, although overall monocyte migration likely rises by other mechanisms

- The two serological subsets MPO-AAV and PR3-AAV exhibit differences in monocyte activation and chemokine receptor expression
Differential and temporally dynamic involvement of primate amygdala nuclei in face animacy and reward information processing
Authors: Kuraoka Koji , Nakamura Kae
Published: January 2024

Decision-making is influenced by both expected reward and social factors, such as who offered the outcomes. Thus, although a reward might originally be independent from social factors, the two elements are closely related. However, whether and how they are processed separately or conjointly remains unclear. Here, we show that neurons in distinct sub-nuclei of the amygdala encode expected reward and face animacy, which is a vital aspect of face perception. Although these encoding processes are distinct, they rely on partially shared neuronal circuits with characteristic temporal dynamics.

Two male macaque monkeys made saccades under different social and reward contexts, created by presenting facial images with independent attributes: animacy (a monkey or cartoon face) and associated reward (large or small). The stimulus image was presented twice per trial: during the initial stimulus encoding (S1) and before saccades were made (S2). A longer gaze duration for eye region of the monkey versus cartoon images indicated more robust social engagement for realistic faces. During S1, a similar number of lateral nucleus neurons encoded either animacy only with a monkey-image preference, reward only with a large-reward preference, or both. Conversely, neurons in the basal and central nuclei primarily encoded reward, preferring large-versus small-reward associated face images. The reward-dependent modulation was continuous after S1, but was more conspicuous during S1 in the basal nucleus and during both S1 and S2 in the central nucleus. This anatomically- and temporally-specific encoding in the amygdala may underlie the computation and integration of face animacy and reward information.

Significance Statement

Reward and social information are closely related but originally independent, as both influence our decision-making. The amygdala has been associated with both reward and social information coding. However, whether and how they are processed separately or conjointly by individual neurons in the amygdala remains unclear.

We found that neurons in the lateral and basal nuclei encoded face animacy, which is an important aspect of social information, and reward, respectively, during sensory processing. Neurons in the central nucleus encoded reward information during the execution phase. This provides new clarity regarding the mechanisms of separate or integrated social and reward information processing within the amygdala.
Structural insights into peptidoglycan hydrolysis by the FtsEX system inEscherichia coliduring cell division
Authors: Li Jianwei , He Yutong , Xu Xin , Alcorlo Martin , Shi Jian , Roper David I. , A. Hermoso Juan , Sham Lok-To , Luo Min
Published: January 2024

Bacterial cell division relies on precise peptidoglycan (PG) remodelling, a process orchestrated by the FtsEX complex. Comprised of FtsE and FtsX, this complex collaborates with EnvC, a periplasmic lytic enzyme activator, to regulate septal PG hydrolysis by amidases like AmiB. While recent structural investigations, particularly ofPseudomonas aeruginosaFtsEX (PaeFtsEX), have shed light on complex interactions and proposed activation mechanisms, the structural intricacies governing PG degradation by the FtsEX complex and EnvC inEscherichia colicytokinesis remain unexplored. In this study, we present a comprehensive biochemical and structural analysis ofE. coliFtsEX complexes, unveiling a key role for ATP in complex stabilization that extends across bacterial species. Upon EnvC binding, ATPase activity markedly increases. High-resolution structures ofEcoFtsEX, both in the presence and absence of EnvC, reveal a symmetrical conformation ofEcoFtsEX capable of accommodating the inherent asymmetry of EnvC, mediated by flexible loops within the periplasmic domain. Our negative-staining imaging showcases an elongatedEcoFtsEX/EnvC/AmiB complex reminiscent of thePaeFtsEX system. These findings collectively provide intricate insights into the regulation of PG cleavage by FtsEX inE. coli- a pivotal model system used in pilot genetic studies, suggesting a conserved mechanism for precise hydrolase activation in bacteria.
Rapid classification of a novel ALS-causing I149S variant in superoxide dismutase-1
Authors: Shephard VK , Brown ML , Thompson BA , Harpur A , McAlary L
Published: January 2024

Variants of the oxygen free radical scavenging enzyme superoxide dismutase-1 (SOD1) are associated with the neurodegenerative disease amyotrophic lateral sclerosis (ALS). These variants occur in roughly 20% of familial ALS cases, and 1% of sporadic ALS cases. Here, we identified a novel SOD1 variant in a patient in their 50s who presented with movement deficiencies and neuropsychiatric features. The variant was heterozygous and resulted in the isoleucine at position 149 being substituted with a serine (I149S).In silicoanalysis predicted the variant to be destabilising to the SOD1 protein structure. Expression of the SOD1I149Svariant with a C-terminal EGFP tag in neuronal-like NSC-34 cells resulted in extensive inclusion formation and reduced cell viability. Immunoblotting revealed that the intramolecular disulphide between Cys57 and Cys146 was fully reduced for SOD1I149S. Furthermore, SOD1I149Swas highly susceptible to proteolytic digestion, suggesting a large degree of instability to the protein fold. Finally, fluorescence correlation spectroscopy and native-PAGE of cell lysates showed that SOD1I149Swas monomeric in solution in comparison to the dimeric SOD1WT. This experimental data was obtained within 3 months and resulted in the rapid re-classification of the variant from a variant of unknown significance to a clinically actionable likely pathogenic variant.
Community first response for cardiac arrest: comparing phased dispatch policies through Monte Carlo simulation
Authors: van den Berg Pieter L. , Henderson Shane G. , Li Hemeng , Dicker Bridget , Jagtenberg Caroline J.
Published: January 2024

Background

Advanced Community First Responder (CFR) systems send so-called phased alerts: notifications with built-in time delays. The policy that defines these delays affects response times, CFR workload and the number of redundant CFR arrivals.

Methods

We compare policies by Monte Carlo Simulation, estimating the three metrics above. We bootstrap acceptance probabilities and response delays from 29,307 rows of historical data covering all GoodSAM alerts in New Zealand between 1-12-2017 and 30-11-2020. We simulate distances between the patient and CFRs by assuming that CFRs are located uniformly at random in a 1 km circle around the patient, for different CFR densities. Our simulated CFRs travel with a distance-dependent speed that was estimated by linear regression on observed speeds among those responders in the abovementioned data set that eventually reached the patient.

Results

The alerting policy has a large impact on the expected number of alerts sent, the redundant arrivals and the probability of patient survival. CFR app managers can use our results to identify a policy that displays a desirable trade-off between these performance measures.
Physiological JNK3 Concentrations Are Higher in Motor-related and Disease-implicated Brain Regions of C57BL6/J Mice
Authors: Godieva Victoria , Sammoura Ferass , Verrier Paz Sebastian , Han Yoonhee , Di Guida Valentina , Rishel Michael J. , Richardson Jason R. , Chambers Jeremy W.
Published: January 2024

The c-Jun N-terminal kinase 3 (JNK3) is a stress-responsive protein kinase primarily expressed in the central nervous system (CNS). JNK3 exhibits nuanced neurological activities, such as roles in behavior, circadian rhythms, and neurotransmission, but JNK3 is also implicated in cell death and neurodegeneration. Despite the critical role of JNK3 in neurophysiology and pathology, its localization in the brain is not fully understood due to a paucity of tools to distinguish JNK3 from other isoforms. While previous functional and histological studies suggest locales for JNK3 in the CNS, a comprehensive and higher resolution of JNK3 distribution and abundance remained elusive. Here, we sought to define the anatomical and cellular distribution of JNK3 in adult mouse brains. Data reveal the highest levels of JNK3 and pJNK3 were found in the cortex and the hippocampus. JNK3 possessed neuron-type selectivity as JNK3 was present in GABAergic, cholinergic, and dopaminergic neurons, but was not detectable in VGLUT-1-positive glutamatergic neurons and astrocytesin vivo. Intriguingly, higher JNK3 signals were found in motor neurons and relevant nuclei in the cortex, basal ganglia, brainstem, and spinal cord. While JNK3 was primarily observed in the cytosol of neurons in the cortex and the hippocampus, JNK3 appeared commonly within the nucleus in the brainstem. These distinctions suggest the potential for significant differences between JNK3 actions in distinct brain regions and cell types. Our results provide a significant improvement over previous reports of JNK3 spatial organization in the adult CNS and support continued investigation of JNK3’s role in neurophysiology and pathophysiology.
Multiple intersecting pathways are involved in the phosphorylation of CPEB1 to activate translation during mouse oocyte meiosis
Authors: Kunitomi Chisato , Romero Mayra , Daldello Enrico Maria , Schindler Karen , Conti Marco
Published: January 2024

The RNA-binding protein cytoplasmic polyadenylation element binding 1 (CPEB1) plays a fundamental role in the regulation of mRNA translation in oocytes. However, the nature of protein kinase cascades modulating the activity of CPEB1 is still a matter of controversy. Using genetic and pharmacological tools and detailed time courses, here we have reevaluated the relationship between CPEB1 phosphorylation and the activation of translation during mouse oocyte maturation. We show that both the CDK1/MAPK and AURKA/PLK1 pathways converge on the phosphorylation of CPEB1 during prometaphase. Only inactivation of the CDK1/MAPK pathway disrupts translation, while inactivation of either pathway leads to CPEB1 stabilization. However, stabilization of CPEB1 induced by inactivation of the AURKA/PLK1 does not affect translation, indicating that destabilization/degradation can be dissociated from translational activation. The accumulation of the endogenous CCNB1 protein closely recapitulates the translation data. These findings support the overarching hypothesis that the activation of translation in prometaphase in mouse oocytes relies on a CDK1-dependent CPEB1 phosphorylation, and this translational activation precedes CPEB1 destabilization.
A brain-rhythm based computational framework for semantic context and acoustic signal integration in speech processing
Authors: Dogonasheva Olesia , Doelling Keith , Zakharov Denis , Giraud Anne-Lise , Gutkin Boris
Published: January 2024

Unraveling the mysteries of how humans effortlessly grasp speech despite diverse environmental challenges has long intrigued researchers in systems and cognitive neuroscience. This study explores the neural intricacies underpinning robust speech comprehension, giving computational mechanistic proof for the hypothesis proposing a pivotal role for rhythmic, predictive top-down contextualization facilitated by the delta rhythm in achieving time-invariant speech processing. Our Brain-Rhythm-based Inference model, BRyBI, integrates three key rhythmic processes – theta-gamma interactions for parsing phoneme sequences, dynamic delta rhythm for inferred prosodic-phrase context, and resilient speech representations. Demonstrating mechanistic proof-of-principle, BRyBI replicates human behavioral experiments, showcasing its ability to handle pitch variations, time-warped speech, interruptions, and silences in non-comprehensible contexts. Intriguingly, the model aligns with human experiments, revealing optimal silence time scales in the theta- and delta-frequency ranges. Comparative analysis with deep neural network language models highlights distinctive performance patterns, emphasizing the unique capabilities of a rhythmic framework. In essence, our study sheds light on the neural underpinnings of speech processing, emphasizing the role of rhythmic brain mechanisms in structured temporal signal processing – an insight that challenges prevailing artificial intelligence paradigms and hints at potential advancements in compact and robust computing architectures.
The Role of Rhizosphere Microorganisms and CNPS Genes in Shaping Nutritional Traits of Capsicum
Authors: Tao Yu , Zhang Mingxing , Peng Siwen , Long Shiping , Zou Xuexiao , Li Xin
Published: January 2024

The rhizosphere microbiota plays crucial roles in biogeochemical cycling and primary production. However, there is a lack of research exploring the complex relationships between microbiota and their functional traits in pepper rhizospheres, as well as their impact on nutrient cycling processes. Here, we investigated the effects of pepper species on the rhizomicrobiota and functional genes (C/N/P/S) on nutrient absorptions and accumulations in pepper organs. The results revealed that Pepper YZ/BE had higher N content in all compartments, which could be attributed to the presence of enriched N-metabolic microbes (Gaiellales/Leifsonia) and higher expression of N availability-promoting genes (ureC/amoA2/nxrA/napA) in rhizospheres. Additionally, we utilized co-occurrence network analysis and partial least squares path modeling (PLS-PM) to understand the interactions among the variables. The bacterial network exhibited more associations than the fungal network, and the abundance of certain modules positively correlated with the expression of CNPS genes, which thus significantly influenced pepper nutrient content. The PLS-PM analysis demonstrated that taxa abundance in network modules, functional genes, and rhizospheric soil properties collectively explained 92% of the variance in pepper nutrient content. Overall, this study provides valuable experimental and theoretical insights into the effects of rhizosphere microorganisms and CNPS genes on the nutritional traits ofCapsicum.

Highlight

The rizho-bacterial community harbored more robust relationships than the fungal ones, which formed the functional clusters highly linking to the below- and aboveground nutrient properties of pepper species.
The type of inhibition provided by thalamic interneurons alters the input selectivity of thalamocortical neurons
Authors: Djama Deyl , Zirpel Florian , Ye Zhiwen , Moore Gerald , Chue Charmaine , Edge Christopher , Jager Polona , Delogu Alessio , Brickley Stephen G
Published: January 2024

A fundamental problem in neuroscience is how neurons select for their many inputs. A common assumption is that a neuron’s selectivity is largely explained by differences in excitatory synaptic input weightings. Here we describe another solution to this important problem. We show that within the first order visual thalamus, the type of inhibition provided by thalamic interneurons has the potential to alter the input selectivity of thalamocortical neurons. To do this, we developed conductance injection protocols to compare how different types of synchronous and asynchronous GABA release influence thalamocortical excitability in response to realistic patterns of retinal ganglion cell input. We show that the asynchronous GABA release associated with tonic inhibition is particularly efficient at maintaining information content, ensuring that thalamocortical neurons can distinguish between their inputs. We propose a model where alterations in GABA release properties results in rapid changes in input selectivity without requiring structural changes in the network.
Estrogen-related differences in antitumor immunity and the gut microbiome contribute to sexual dimorphism of colorectal cancer
Authors: Lattanzi Georgia , Perillo Federica , Díaz-Basabe Angélica , Caridi Bruna , Amoroso Chiara , Baeri Alberto , Cirrincione Elisa , Ghidini Michele , Galassi Barbara , Cassinotti Elisa , Baldari Ludovica , Boni Luigi , Vecchi Maurizio , Caprioli Flavio , Facciotti Federica , Strati Francesco
Published: January 2024

Colorectal cancer (CRC) is a multifaceted disease whose development and progression varies depending on tumor location, age of patients, infiltration of immune cells within cancer lesions, and the tumor microenvironment. These pathophysiological characteristics are additionally influenced by sex-related differences. The gut microbiome plays a pivotal role in the initiation and progression of CRC, and shapes anti-tumor immune responses but how the responsiveness of the immune system to the intestinal microbiota may contribute to the sexual dimorphism of CRC is largely unknown. Here, we studied survival, tumor-infiltrating immune cell populations and tumor-associated microbiome of a cohort of n=184 male and female CRC patients and functionally tested the immune system-microbiome interactions inin vivoandin vitromodels of the disease. High-dimensional single-cell flow cytometry showed that female patients are enriched by tumor-infiltrating iNKT cells but depleted by cytotoxic T lymphocytes. The enrichment of oral pathobionts and a reduction of β-glucuronidase activity are distinctive traits characterizing the gut microbiome of women affected by CRC. Functional assays using a collection of human primary iNKT cell lines demonstrated that the gut microbiota of female patients functionally impairs iNKT cell anti-tumor functions interfering with the granzyme-perforin cytotoxic pathway. These results highlight a sex-dependent functional relationship between the gut microbiome, estrogen metabolism, and the decline of cytotoxic T cell responses, contributing to the sexual dimorphism observed in CRC patients with relevant implications for precision medicine and the design of targeted therapeutic approaches addressing sex bias in cancer.
Novel FKBP12 ligand promotes functional improvement in SOD1G93AALS mice
Authors: Moreno-Martinez Laura , Gaja-Capdevila Núria , Mosqueira-Martín Laura , Herrando-Grabulosa Mireia , Gonzalez-Imaz Klaudia , Calvo Ana C. , Sagartzazu-Aizpurua Maialen , Moreno-García Leticia , Fuentes Jose Manuel , Acevedo-Arozena Abraham , Aizpurua Jesús María , Miranda José Ignacio , de Munain Adolfo López , Vallejo-Illarramendi Ainara , Navarro Xavier , Osta Rosario , Gil-Bea Francisco Javier
Published: January 2024

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with limited treatment options. ALS pathogenesis involves intricate processes within motor neurons (MNs), characterized by dysregulated Ca2+influx and buffering in early ALS-affected MNs. This study proposes the modulation of ryanodine receptors (RyRs), key mediators of intracellular Ca2+, as a therapeutic target. A novel class of novel FKBP12 ligands that show activity as cytosolic calcium modulators through stabilizing RyR channel activity, were tested in the SOD1G93Amouse model of ALS. Different outcomes were used to assess treatment efficacy including electrophysiology, histopathology, neuromuscular function, and survival. Among the novel FKBP12 ligands, MP-010 was chosen for its central nervous system availability. Chronic administration of MP-010 to SOD1G93Amice produced a dose-dependent preservation of motor nerve conduction, with the 61 mg/kg dose significantly delaying the onset of motor impairment. This was accompanied by improved motor coordination, increased innervated endplates, and significant preservation of MNs in the spinal cord of treated mice. Notably, MP-010 treatment significantly extended lifespan by an average of 10 days compared to vehicle. In conclusion, FKBP12 ligands, particularly MP-010, exhibit promising neuroprotective effects in ALS, highlighting their potential as novel therapeutic agents. Further investigations into the molecular mechanisms and clinical translatability of these compounds are needed for their application in ALS treatment.
Epigenetic control of multiple genes with a single lentiviral vector encoding transcriptional repressors fused to compact zinc finger arrays
Authors: Monteferrario Davide , David Marion , Tadi Satish K. , Zhou Yuanyue , Marchetti Irène , Jeanneau Caroline , Saviane Gaëlle , Dupont Coralie F. , Martelli Angélique E. , Truong Lynn , Eshleman Jason , Ng Colman , Huston Marshall , Davis Gregory D. , Fontenot Jason D. , Reik Andreas , de la Rosa Maurus , Fenard David
Published: January 2024

Gene silencing without gene editing holds great potential for the development of safe therapeutic applications. Here, we describe a novel strategy to concomitantly repress multiple genes using zinc finger proteins fused to Krüppel-Associated Box repression domains (ZF-Rs). This was achieved via the optimization of a lentiviral system tailored for the delivery of ZF-Rs in hematopoietic cells. We showed that an optimal design of the lentiviral backbone is crucial to multiplex up to three ZF-Rs or two ZF-Rs and a chimeric antigen receptor. ZF-R expression had no impact on the integrity and functionality of transduced cells. Furthermore, gene repression in ZF-R-expressing T cells was highly efficientin vitroandin vivoduring the entire monitoring period (up to ten weeks), and it was accompanied by epigenetic remodeling events. Finally, we described an approach to improve ZF-R specificity to illustrate the path towards the generation of ZF-Rs with a safe clinical profile. In conclusion, we successfully developed an epigenetic-based cell engineering approach for concomitant modulation of multiple gene expressions that bypass the risks associated with DNA editing.
PatternJ: an ImageJ toolset for the automated and quantitative analysis of regular spatial patterns found in sarcomeres, axons, somites, and more
Authors: Blin Mélina Baheux , Loreau Vincent , Schnorrer Frank , Mangeol Pierre
Published: January 2024

Regular spatial patterns are ubiquitous forms of organization in nature. In animals, regular patterns can be found from the cellular scale to the tissue scale, and from early stages of development to adulthood. To understand the formation of these patterns, how they form and mature, and how they are affected by perturbations, a precise quantitative description of the patterns is essential. However, accessible tools that offer in-depth analysis without the need for computational skills are lacking for biologists. Here we present PatternJ, a novel toolset to analyze regular pattern organizations precisely and automatically. This toolset, to be used with the popular imaging processing program ImageJ/Fiji, facilitates the extraction of key geometric features within and between pattern repeats. We validated PatternJ on simulated data and tested it on images of sarcomeres in insect muscles and cardiomyocytes, actin rings in neurons, and somites in zebrafish embryos obtained using confocal fluorescence microscopy, STORM, electron microscopy, and bright-field imaging. We show that the toolset delivers subpixel feature extraction reliably even with images of low signal-to-noise ratio. PatternJ’s straightforward use and functionalities make it valuable for various scientific fields requiring quantitative pattern analysis, including the sarcomere biology of muscles or the patterning of mammalian axons, speeding up discoveries with the bonus of high reproducibility.
Histological analysis of Scots pine (Pinus sylvestrisL.) seedlings in response to root rot pathogenHeterobasidion annosuminoculation
Authors: Youssef Khaled , Marttila Salla
Published: January 2024

Heterobasidionroot rot is one of the most serious and economically destructive forest diseases in the Northern Hemisphere. Although several studies have explored the genetic and chemical responses of Scots pine toHeterobasidionspp. infection, the histological defense responses of this species remain poorly understood. In this study, we investigated the histological responses of three-year-old Scots pine seedlings toHeterobasidion annosuminoculation and a wounding treatment with no inoculation, focusing on lesion length and traumatic resin-duct characteristics (density, size). Our results showed thatH. annosum-inoculated seedlings exhibited significantly more browning necrotic lesions than wounded seedlings. Traumatic resin duct density was significantly higher inH. annosum-inoculated seedlings compared to wounded seedlings, particularly within the first two cm from the inoculation point. However, as the distance from the inoculation point increased, the resin duct density decreased. Notably, there were neither statistically significant differences in the mean size of traumatic and constitutive resin ducts between the two treatments, nor within theH. annosuminoculation treatment itself. In contrast, within the wound treatment, the mean size of traumatic resin ducts was found to be significantly smaller than that of constitutive resin ducts. Furthermore, traumatic resin ducts did not prove to be reliable markers for datingH. annosuminfection in Scots pine. Overall, this study advances knowledge about Scots pine’s histological defense mechanisms againstH. annosuminvasion, which has significant implications.