bluuebunny/crossref_metadata_2025_split huggingface dataset:
What is needed for the roll-out of psychedelic treatments?
Authors: Xenakis Stephen N. , Shannon Scott M. 
Published: May 2024

Purpose of review
The pace of psychedelic treatments continues to increase. Regulation and coherent clinical guidance have not been established. A philosophical divide limits effective resolution of a practice delivery quandary: is this primarily a pharmacological or psychotherapeutic intervention?

Recent findings
Lykos (formerly MAPS) has submitted its new drug application (NDA) request to the FDA for 3-4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for PTSD and is expecting a response by the summer of 2024. Australia endorsed psilocybin and MDMA for regulated use in 2023. Multiple phase II and III clinical trials are also being conducted in the United States and Europe to study the use of psilocybin. Currently, Colorado and Oregon have legalized psilocybin in different manners. In Colorado, plants containing psilocybin, ibogaine, dimethyltryptamine (DMT) and mescaline (other than peyote) are now legal to possess, share and cultivate. Guidelines for regulated treatment with psilocybin containing mushrooms are in process with service delivery to begin early in 2025. In Oregon, clients must complete a preparation session with a licensed facilitator before consuming psilocybin products at a licensed service center. A prescription is not required. It is expected that other states will follow suit with a ballot measure likely in Massachusetts this year. Additionally, in the United States, the DEA, state boards, pharmaceutical distributors, and professional liability carriers all share mounting concerns about the in-home use of compounded ketamine used as a psychedelic therapeutic via remote prescribing.

Summary
Psychedelic treatments are rapidly entering the mainstream of medical care delivery in the United States. Clinical guidelines are urgently needed to ensure well tolerated practice and coherent regulation. The delivery of this guidance is limited by a core philosophical disagreement. Resolution of this conflict will be needed to deliver coherent clinical guidelines. Current research and clinical experience provide a solid foundation for practical clinical guidance and the introduction of psychedelics into healthcare.
Anatomics MLT, an AI tool for large scale quantification of ultrastructural traits
Authors: Brookhouse Aaron , Ji Yuting , Knoblauch Jan , Gaburak Petr , Wager Brittney M. , Lin Zudi , Kunz Hans-Henning , Gebremedhin Assefaw H. , Pfister Hanspeter , Peters Winfried S. , Wei Donglai , Knoblauch Michael 
Published: May 2024

AbstractThe ever increasing breadth of biological knowledge has led to recent efforts to combine information from various fields into cell– or tissue atlases. Anatomical features are the structural basis for such efforts, but unfortunately large scale analysis of subcellular anatomical traits is currently a missing feature. Similarly, small phenotypic alterations of organelle– or cell-specific anatomical traits, such as an increase of the total volume or the number of mitochondria in response to certain stimuli, are currently hard to quantify. To provide tools to extract quantitative information from available 3D microscopic datasets generated with methods such as serial block face scanning electron microscopy we a) developed much improved fixation and embedding protocols for plants to drastically reduce processing artifacts and b) generated an easy-to-use AI tool for quantitative analysis and visualization of large-scale data sets. We make this tool available as open source.
AmpliconSuite: an end-to-end workflow for analyzing focal amplifications in cancer genomes
Authors: Luebeck Jens , Huang Edwin , Kim Forrest , Liefeld Ted , Dameracharla Bhargavi , Ahuja Rohil , Schreyer Daniel , Prasad Gino , Adamaszek Michał , Kenkre Rishaan , Agashe Tushar , Torvi Devika , Tabor Thorin , Giurgiu Mădălina , Kim Soyeon , Kim Hoon , Bailey Peter , Verhaak Roel G.W. , Deshpande Viraj , Reich Michael , Mischel Paul S. , Mesirov Jill , Bafna Vineet 
Published: May 2024

ABSTRACTFocal amplifications in the cancer genome, particularly extrachromosomal DNA (ecDNA) amplifications, are emerging as a pivotal event in cancer progression across diverse cancer contexts, presenting a paradigm shift in our understanding of tumor dynamics. Simultaneously, identification of the various modes of focal amplifications is bioinformatically challenging. We present AmpliconSuite, a collection of tools that enables robust identification of focal amplifications from whole-genome sequencing data. AmpliconSuite includes AmpliconSuite- pipeline; utilizing the AmpliconArchitect (AA) method, and AmpliconRepository.org; a community- editable website for the sharing of focal amplification calls. We also describe improvements made to AA since its initial release that improve its accuracy and speed. As a proof of principle, we utilized publicly available pan-cancer datasets encompassing 2,525 tumor samples hosted onAmpliconRepository.orgto illustrate important properties of focal amplifications, showing ecDNA has higher copy number, and stronger oncogene enrichment, compared to other classes of focal amplifications. Finally, we illustrate how AmpliconSuite-pipeline enables delineation of the various mechanisms by which ecDNA forms.
KRas, in addition to Tp53 is a driver for early carcinogenesis and a molecular target in a mouse model of invasive gastro-esophageal adenocarcinoma
Authors: Anand Akanksha , Schömig Linus , Lange Sebastian , Tran Li , Flisikowski Krzysztof , Öllinger Rupert , Rad Roland , Vieth Michael , Steiger Katja , Baumeister Theresa , Strangmann Julia , Algül Hana , Ciecielski Katrin , Böttcher Katrin , Fang Hsin-Yu , Carvalho Marcos Jόse Braz , Mohammad-Shahi Donja Sina , Gerland Sophie , Proaño-Vasco Andrea , Schnieke Angelika , Thimme Robert , Schmid Roland M. , Wang Timothy C. , Quante Michael 
Published: May 2024

AbstractObjectiveThe incidence of gastro-esophageal adenocarcinoma (GEAC) has increased dramatically and is associated with Barrett’s Esophagus (BE). Gastric cardia progenitors are the likely origin for BE and GEAC. Here we analyzep53, Rb1andKrasalterations in Lgr5 progenitor cells during carcinogenesis.DesignWe introduced single and combined genetic alterations (p53, Rb1andKras) in Lgr5-expressing progenitor cells at the inflamed gastroesophageal junction in the L2-IL1b (L2) mouse model crossed toLgr5-CreERTmice. Forin-vitrotreatment we utilized mouse and human 3D organoids.ResultsInactivation ofTp53orRb1alone (L2-LP and L2-LR mice) resulted in metaplasia, and mild dysplasia, while expression ofKrasG12D(L2-LK) accelerated dysplasia in L2-IL1b mice. Dual induction of genetic alteration in L2-LPR, L2-LKP and L2-LKR mice confirmed the accelerating role of mutantKras, with the development of invasive cancer in mice with combinedTp53andKrasalteration. All three genetic events in cardia progenitor cells generated invasive cancer at 6 months of age, with chromosomal instability (CNV). The dominant role ofKrasprompted us to treat with a SHP2 inhibitor in combination with an ERK or MEK inhibitor, leading to reduced growth inKrasmutant organoids. SHP2 and MEK inhibitionin-vivoreducedKrasdependent tumor formation.ConclusionIn the first invasive GEAC mouse model,Krasmutation in combination with loss of tumor suppressor genes Tp53 or Rb1 emerges as a key player in GEAC and with importance of p53 and Rb1 in promoting metaplasia. Targeting this SHP2/MEK/KRAS pathway represents a promising therapeutic option forKrasaltered GEAC.What is already known on this topicThe increased incidence of GEAC is challenging current screening and surveillance strategies. Therapeutic and preventive options are limited due to a lack of knowledge on the role of genetic alterations commonly associated with GEAC and their function during progression to dysplasia.What this study addsWe generate the first invasive GEAC model and show thatKRASat least in combination with a second genetic alterations (Tp53 and/or Rb1) may be a driver of tumorigenesis, and targeting KRAS alterations could be a promising now treatment substitution.How this study might affect research, practice or policyTargeting KRAS alterations will be important for GEAC, especially as specific KRAS inhibitor are on the horizon. In addition, a concept of single genetic alteration inducing metaplasia as an adaptation to chronic inflammation might emerge as an important factor for surveillance.
Myosin ATPase inhibition fails to rescue the metabolically dysregulated proteome of nebulin-deficient muscle
Authors: Laitila Jenni , Seaborne Robert A.E. , Ranu Natasha , Kolb Justin S. , Wallgren-Pettersson Carina , Witting Nanna , Vissing John , Vilchez Juan Jesus , Zanoteli Edmar , Palmio Johanna , Huovinen Sanna , Granzier Henk , Ochala Julien 
Published: May 2024

AbstractNemaline myopathy (NM) is a genetic muscle disease, primarily caused by mutations in theNEBgene (NEB-NM) and with muscle myosin dysfunction as a major molecular pathogenic mechanism. Recently, we have observed that the myosin biochemical super-relaxed state was significantly impaired inNEB-NM, inducing an aberrant increase in ATP consumption and remodelling of the energy proteome in diseased muscle fibres. As the small-molecule Mavacamten is known to promote the myosin super-relaxed state and reduce the ATP demand, here, we tested its potency in the context ofNEB-NM. We first conductedin vitroexperiments in isolated single myofibres from patients and found that Mavacamten successfully reversed the myosin ATP over-consumption. Following this, we assessed its short-termin vivoeffects by using the conditional nebulin knock-out (cNebKO) mouse model and by subsequently performing global proteomics profiling in dissected soleus myofibres. After a four-week treatment period, we observed a remodelling of a large number of proteins in both cNebKO mice and their wild-type siblings. Nevertheless, these changes were not related to the energy proteome, indicating that short-term Mavacamten treatment is not sufficient to properly counterbalance the metabolically dysregulated proteome of cNebKO mice. Taken together, our findings emphasize Mavacamten potencyin vitrobut challenge its short-term efficacyin vivo.Key points summaryNo cure exists for nemaline myopathy, a type of genetic skeletal muscle disease mainly derived from mutations in genes encoding myofilament proteins.Applying Mavacamten, a small molecule directly targeting the myofilament, to isolated membrane-permeabilized muscle fibres from human patients restored myosin energetic disturbances.Treating a mouse model of nemaline myopathyin vivowith Mavacamten for four weeks, remodeled the skeletal muscle fibre proteome without any noticeable effects on energetic proteins.Short-term Mavacamten treatment may not be sufficient to reverse the muscle phenotype in nemaline myopathy.
Assembly of a segrosome by a CTP-independent ParB-like protein
Authors: Sukhoverkov Kirill V. , Balaguer-Perez Francisco , Aicart-Ramos Clara , Maqbool Abbas , Chandra Govind , Moreno-Herrero Fernando , Le Tung B. K. 
Published: May 2024

ABSTRACTThe ATP– and CTP-dependent ParA-ParB-parSsegrosome is a macromolecular complex that segregates chromosomes/plasmids in most bacterial species. CTP binding and hydrolysis enable ParB to slide on DNA and to bridge and condense DNA, thereby dictating the size and dynamics of the tripartite ParABScomplex. Several other evolutionarily distinct systems can also segregate DNA, although the full diversity of bacterial DNA partition systems is not yet known. Here, we identify a CTP-independent ParABSsystem that maintains a conjugative plasmid SCP2 in the filamentous bacteriumStreptomyces coelicolor. We demonstrate that an SCP2 ParB-like protein, ParT, loads onto DNA at an 18-bpparSsite and diffuses away to the adjacent DNA despite lacking an apparent CTPase domain and detectable NTPase activity. We further show thatparSDNA stimulates ParT transition from loading to a diffusing state to accumulate on DNA, and ParT activates the ATPase activity of its cognate partner protein ParA. We also identify numerous structural homologs of ParT, suggesting that CTP-independent diffusion on DNA might be widespread in bacteria despite being previously unappreciated. Overall, our findings uncover a CTP-independent DNA translocation as an alternative and unanticipated mechanism for the assembly of a bacterial DNA segregation complex and suggest that CTP binding and hydrolysis is not a fundamental feature of ParABS-like systems.
Evolution towards extremely high β-lactam resistance inMycobacterium abscessusoutbreak strains
Authors: le Run Eva , Tettelin Hervé , Holland Steven M. , Zelazny Adrian M. 
Published: May 2024

AbstractTreatment ofMycobacterium abscessuspulmonary disease requires multiple antibiotics including intravenous β-lactams (e.g., imipenem, meropenem).M. abscessusproduces a β-lactamase (BlaMab) that inactivates β-lactam drugs but less efficiently carbapenems. Due to intrinsic and acquired resistance inM. abscessusand poor clinical outcomes, it is critical to understand the development of antibiotic resistance both within the host and in the setting of outbreaks.We compared serial longitudinally collectedM. abscessussubsp.massilienseisolates from the index case of a CF center outbreak and four outbreak-related strains. We found strikingly high imipenem resistance in the later patient isolates, including the outbreak strain (MIC >512 µg/ml). The phenomenon was recapitulated upon exposure of intracellular bacteria to imipenem. Addition of the β-lactamase inhibitor avibactam abrogated the resistant phenotype. Imipenem resistance was caused by an increase in β-lactamase activity and increasedblaMabmRNA level. Concurrent increase in transcription of precedingppiAgene indicated upregulation of the entire operon in the resistant strains.Deletion of the porinmspAcoincided with the first increase in MIC (from 8 to 32 µg/ml). A frameshift mutation inmsp2responsible for the rough colony morphology, and a SNP in ATP-dependent helicasehrpAco-occurred with the second increase in MIC (from 32 to 256 µg/ml). Increased BlaMabexpression and enzymatic activity may have been due to altered regulation of theppiA-blaMaboperon by the mutated HrpA alone, or in combination with other genes described above. This work supports using carbapenem/β-lactamase inhibitor combinations for treatingM. abscessus, particularly imipenem resistant strains.
Impact of the COVID-19 pandemic on antidiabetic drugs initiation in Sweden, an interrupted time series study
Authors: Khanyk Nataliia , Nyberg Fredrik , Wettermark Björn , Li Huiqi , Eeg-Olofsson Katarina , Gudbjornsdottir Soffia , Hajiebrahimi Mohammadhossein 
Published: May 2024

AbstractAimTo investigate the impact of the COVID-19-pandemic on antidiabetic drug initiationMethodsUsing Swedish national health registers, an interrupted time series study for all first-time dispensed antidiabetic drugs was performed. A minimum 14-month washout period was used. We calculated monthly cumulative incidence of antidiabetic drug initiations per 1000 population and estimated trends before and after the onset of the pandemic using segmented regression analysis.ResultsAmong 167,889 participants between 1Mar2019 and 30Nov2021, male sex (53%), age 18-64 (55.3%), unmarried status (52.5%), upper secondary education level (46.2%), and being employed (53.5%) were the most frequent characteristics. Mar2020, there was an immediate level drop in antidiabetic drug initiation (β2=-0.087%, P=0.01); however, the trend exhibited a rapid increase thereafter. Significant immediate level drops were identified for DPP4i (−0.087%, P=0.01), GLP1a (−0.008%, P=0.01) and SGLT2i (−0.033%, P=0.003). Older people (≥65) showed the largest immediate drop for antidiabetic drug initiation (−0.272%, P=0.003). SGLT2i demonstrated an increasing pattern both before and after the pandemic while metformin did reveal an increasing pattern among patients ≥65 years old after the pandemic.ConclusionThe results identified an immediate level drop at the onset of the pandemic for any antidiabetic drug initiation, but the trend increased rapidly thereafter.
Endovascular thrombectomy: an effective and safe therapy for perioperative ischemic stroke
Authors: Wang Feng , Xu Xiaoping , Zheng Ling , Zhong Jiawei , Wang En , Liu Yang , Ke Shaofa 
Published: May 2024

AbstractBackgroundPerioperative ischemic stroke is a rare but devastating complication. Mechanical thrombectomy is a promising therapeutic method, but very little data is available on its efficacy and safety. This study aims to answer this question by comparing the clinical outcomes of perioperative and community-onset stroke patients after endovascular therapy.MethodsA retrospective cohort study was conducted on a total of 35 perioperative and 584 community-onset acute ischemic stroke patients who underwent endovascular thrombectomy at our hospital over the past 3.5 years. The recanalization rate, clinical recovery and cerebral hemorrhage within 90 days after therapy were compared between these two patient groups.ResultsEndovascular thrombectomy provided perioperative and community-onset ischemic stroke patients with comparable rates of successful reperfusion (mTICI ≥ 2b grade) (97.1% vs. 97.3%;P= 0. 967) and favorable functional recovery (mRS ≤ 2) (51.4% vs. 43.3%,P= 0.348), with no increase in severe intracranial hemorrhage (0% vs. 2.6% and 1.0%, for hematoma ≥ 30% of infarcted tissue and intraventricular hemorrhage, respectively) within 90 days. In addition, perioperative stroke patients had higher prevalence of atrial fibrillation (42.9 % vs. 26.7 %;P= 0.038) and intracranial cerebral artery stenosis without clear embolism (17.1 % vs. 3.8 %;P< 0.001) than community-onset stroke patients.ConclusionsEndovascular thrombectomy is an effective and safe therapeutic approach for patients with perioperative ischemic stroke, although the results need to be validated by further studies with larger populations. Atrial fibrillation and large artery stenosis may contribute to the pathogenesis of perioperative ischemic stroke.
CharacterisingStaphylococcus aureusgenomic epidemiology with Multilevel Genome Typing
Authors: Cheney Liam , Payne Michael , Kaur Sandeep , McKew Genevieve , Lan Ruiting 
Published: May 2024

AbstractStaphylococcus aureusis a major source of both hospital and community acquired infections, and is the leading source of skin and soft tissue infections worldwide. Advances in whole genome sequencing (WGS) technologies have recently generated large volumes ofS. aureusWGS data. The timely classification ofS. aureusWGS data with genomic typing technologies has the potential to describe detailed genomic epidemiology at large and small scales. In this study, a multilevel genome typing (MGT) scheme comprised of 8 levels of multilocus sequence typing schemes of increasing resolution was developed forS. aureusand used to analyse 50,481 publicly available genomes. Application of MGT toS. aureusepidemiology was showcased in three case studies. Firstly, the population structure of the globally disseminated sequence type ST8 were described by MGT2, which was compared withSpatyping. Secondly, MGT was used to characterise MLST ST8 - PFGE USA300 isolates that colonised multiple body sites of the same patient. Unique STs from multiple MGT levels were able to group isolates of the same patient, and the highest resolution MGT8 separated isolates within a patient that varied in predicted antimicrobial resistance. Lastly, MGT was used to describe the transmission of MLST ST239 - SCCmecIII throughout a single hospital. MGT STs were able to describe both isolates that had spread between wards and also isolates that had colonised different reservoirs within a ward. TheS. aureusMGT describes large- and small-scaleS. aureusgenomic epidemiology with scalable resolutions using stable and standardised ST assignments. TheS. aureusMGT database is online (https://mgtdb.unsw.edu.au/staphylococcus) and is capable of tracking new and existing clones to facilitate the design of new strategies to reduce the global burden ofS. aureusrelated diseases.
Introgression impacts the evolution of bacteria, but species borders are rarely fuzzy
Authors: Diop Awa , Bobay Louis-Marie 
Published: May 2024

AbstractMost bacteria engage in gene flow and that this may act as a force maintaining species cohesiveness like it does in sexual organisms. However, introgression (gene flow between the genomic backbone of distinct species) has been reported in bacteria and is associated with fuzzy species borders in some lineages, but its prevalence and impact on the delimitation of bacterial species has not been systematically characterized. Here, we quantified the patterns of introgression across 50 major bacterial lineages. Our results reveal that bacteria present various levels of introgression, with an average of 2% of introgressed core genes and up to 12% inCampylobacter. Furthermore, our results show that some species are more prone to introgression than others within the same genus and introgression is most frequent between highly related species. We found evidence that the various levels of introgression across lineages are likely related to ecological proximity between species. Introgression can occasionally lead to fuzzy species borders, although many of these cases are likely instances of ongoing speciation. Overall, our results indicate that introgression has substantially shaped the evolution and the diversification of bacteria, but this process does not substantially blur species borders.
Intestinal microbiome dysbiosis increasesMycobacteriapulmonary colonization in mice by regulating theNos2-associated pathways
Authors: Han MeiQing , Wang Xia , Su Lin , Pan Shiqi , Liu Ningning , Li Duan , Liu Liang , Cui JunWei , Zhao Huajie , Yang Fan 
Published: May 2024

AbstractIncreasing researches reveal gut microbiota was associated with the development of tuberculosis. How to prevent or reduceMycobacterium tuberculosiscolonization in the lungs is a key measure to prevent tuberculosis. However, the data on gut microbiota preventingMycobacteriumcolonization in the lungs were scarce. Here, we established the clindamycin-inducing intestinal microbiome dysbiosis and fecal microbial transplantation models in mice to identify gut microbiota’s effect onMycobacterium’s colonization in the mouse lungs and explore its potential mechanisms. The results showed that clindamycin treatment altered the diversity and composition of the intestinal bacterial and fungal microbiome, weakened the trans-kingdom network interactions between bacteria and fungi, and induced gut microbiome dysbiosis in the mice. Gut microbiota dysbiosis increases intestinal permeability and enhances the susceptibility ofMycobacteriumcolonization in the lungs of mice. The potential mechanisms were gut microbiota dysbiosis altered the lung transcriptome and increasedNos2expression through the “gut-lung axis”.Nos2high expression disrupts the intracellular antimicrobial and anti-inflammatory environment by increasing the concentration of NO, decreasing the levels of ROS andDefb1in the cells, and resulting in promotingMycobacteriacolonization in the lungs of mice. The present study raises a potential strategy for reducing the risks ofMycobacteriainfections and transmission by regulating the gut microbiome balance.