bluuebunny/crossref_metadata_2025 huggingface dataset:
Neuroinflammatory syndromes in children
Authors: Hauptman Aaron J. , Ferrafiat Vladimir
Published: January 2023

Purpose of review

Neuropsychiatric symptoms due to paediatric neuroinflammatory diseases are increasingly recognized and reported. Psychiatrists are crucial in front-lines identification, diagnosis and care of individuals with disorders such as autoimmune encephalitis and management of long-term neurobehavioral sequelae. This review summarizes recent literature on autoimmune and post-infectious encephalitis, discusses special considerations in children with neurodevelopmental conditions and presents a paradigm for evaluation and management.

Recent findings

There is a growing body of evidence on neuropsychiatric symptom burdens of paediatric neuroinflammatory diseases. A particular development is the evolution of diagnostic and treatment guidelines for conditions such as autoimmune encephalitis, which take into account phenotypes of acute, short-term and long-term sequelae. Interest in inflammatory sequelae of viral illness, such as SARS-CoV-2, in children remains in early development.

Neuroimmunological disease data are constantly evolving. New recommendations exist for multiple common neuroimmunological disorders with behavioural, emotional, cognitive and neurological sequelae. Anti-NMDA receptor encephalitis now has well-recognized patterns of symptom semiology, diagnostic and treatment recommendations, and outcome patterns. Recognizing psychiatric symptoms heralding autoimmune brain disease and understanding neuropsychiatric sequelae are now a crucial skill set for paediatric psychiatrists. Exploration of inflammatory features of other diseases, such as genetic syndromes, is a burgeoning research area.
Characterization of Shigella flexneri in Northern Vietnam in 2012 –2016
Authors: Nguyen Dong Tu , Morita Masatomo , Ngo Tuan Cuong , Le Thanh Huong , Le Dang Hai , Nguyen Hoai Thu , Akeda Yukihiro , Ohnishi Makoto , Izumiya Hidemasa
Published: January 2023

ntroduction: Shigellosis remains a considerable public health concern in developing countries. Shigella flexneri and Shigella sonnei are prevalent worldwide and S. sonnei has been replacing S. flexneri.
Gap Statement: S. flexneri still causes outbreaks in Northern Vietnam and limited information is available on its genetic characteristics.
Aim: This study aimed to characterize the genetic characteristics of S. flexneri strains from Northern Vietnam.
Methodology: This study used 17 isolates from eight incidents, collected in Northern Vietnam between 2012 and 2016. The samples were subjected to whole genome sequencing (WGS), molecular serotyping, cluster analysis, and identification of antimicrobial resistance genes. Additionally, phylogenetic analysis was performed including isolates from previous studies.
Results: Clusters were identified according to spatiotemporal backgrounds. The results suggested that two incidents in Yen Bai province in 2015 and 2016 were derived from a very recent common ancestor. All isolates belonged to phylogroup (PG) 3, which was divided into two sub-lineages. Thirteen of 17 isolates, including those from the Yen Bai incidents, belonged to sub-lineage Sub-1 and were serotyped as 1a. The remaining four isolates belonged to sub-lineage Sub-2 and were the globally predominant serotype 2a. The Sub-1 S. flexneri isolates possessed the gtrI gene, which encodes the glycosyl transferase that determines serotype 1a, with bacteriophage elements in the vicinity.
Conclusion: This study revealed two PG3 sub-lineages of S. flexneri in Northern Vietnam, of which Sub-1 might be specific to the region.
Anaeromicropila herbilytica gen. nov., sp. nov., a plant polysaccharide-decomposing anaerobic bacterium isolated from anoxic soil subjected to reductive soil disinfestation, and reclassification of Clostridium populeti as Anaeromicropila populeti comb. nov.
Authors: Ueki Atsuko , Tonouchi Akio , Kaku Nobuo , Ueki Katsuji
Published: January 2023

An obligately anaerobic bacterial strain (TB5T) was isolated from a soil sample subjected to reductive or biological soil disinfestation. Cells of the strain were Gram-stain-positive, spore-forming and motile rods. The strain grew at 15–40 °C (optimum, 37 °C) and pH 5.4–7.5 (optimum, pH 7.3). Strain TB5Tutilized a wide variety of carbohydrates including polysaccharides (cellulose, xylan, starch, inulin, glucomannan and laminarin) and organic acids. Acetate, ethanol, H2 and CO2 were products from the substrates utilized. The major components of the cellular fatty acids were C16 : 1
 ω7c DMA, C16 : 0 DMA and C18 : 1
 ω7c DMA. The diagnostic amino acid of the cell-wall peptidoglycan was meso-diaminopimelic acid. The closest related species to strain TB5T based on 16S rRNA gene sequences was

Clostridium populeti

743AT (95.4 % sequence similarity). The genome size of strain TB5T was 5.09 Mb and the genomic DNA G+C content was 32.7 mol%. Strain TB5T had genes encoding polysaccharide-decomposing enzymes such as cellulase, xylanase, β-glucosidase and β-mannosidase in the genome. Based on the phylogenetic, genomic and phenotypic data, a novel species of a novel genus in the family

Lachnospiraceae

, Anaeromicropila herbilytica gen. nov., sp. nov., is proposed to accommodate the strain. The type species is Anaeromicropila herbilytica with strain TB5T (=NBRC 112093T=DSM 110037T) as the type strain. For the closest related species

C. populeti

, Anaeromicropila populeti comb. nov. is proposed with an emended description of the species.
Paenibacillus rhizolycopersici sp. nov., an oligotrophic bacterium isolated from a tomato plant in China
Authors: Thin Kyu Kyu , He Shan-Wen , Ma Rong , Wang Xing , Han Ji-Gang , Zhang Xiao-Xia
Published: January 2023

A Gram-positive, rod-shaped, motile, endospore-forming strain, DXFW5T, was isolated from the rhizosphere soil of tomato. Strain DXFW5T grew at 20–50 °C (optimum, 25–37 °C), pH 5–8 (optimum, pH 7) and in the presence of 3 % NaCl. It was positive for catalase and oxidase. Phylogenetic analysis using 16S rRNA gene sequences showed this strain was most closely related to

Paenibacillus timonensis

DSM 16943T (98.0 %) and

Paenibacillus barengoltzii

DSM 22255T (97.4 %). The DNA G+C content was 52.9 mol%. The digital DNA–DNA hybridization values between strain DXFW5T and

P. timonensis

DSM 16943T,

P. barengoltzii

DSM 22255T and

P. macerans

DSM 24T were 33.1, 24.9 and 21.2 %, respectively. The average nucleotide identity values between strain DXFW5T and

P. timonensis

DSM 16943T
, P. barengoltzii DSM 22255T and

P. macerans

DSM 24T were 86.93, 81.77 and 75.98 %, respectively. The major fatty acids were anteiso-C15 : 0 (55.1 %), iso-C16 : 0 (13.2 %) and C16 : 0 (10 %). The polar lipids of strain DXFW5T consisted of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine two unidentified phospholipids and three unidentified lipids. MK-7 was the major isoprenoid quinone. Based on these results, it was concluded that the isolate represents a novel species of the genus Paenibacillus, for which the name Paenibacillus rhizolycopersici sp. nov. is proposed, with DXFW5T (=ACCC 61751T=JCM 34488T) as the type strain.
Longitudinal detection of prion shedding in nasal secretions of CWD-infected white-tailed deer
Authors: Kraft Caitlyn N. , Denkers Nathaniel D. , Mathiason Candace K. , Hoover Edward A.
Published: January 2023

Chronic wasting disease (CWD) is an emergent prion disease spreading in cervid populations in North America, South Korea and Scandinavia. Rapid detection of CWD prions shed by live animals using minimally invasive methods remains an important need. Previous studies in deer, elk and hamsters have demonstrated prion replication in the nasal olfactory mucosa, yet the temporal profile of CWD prion shedding in nasal secretions has not been well characterized. Here we report nasal prion shedding in 18 deer orally exposed to low doses of CWD prions and monitored longitudinally by several parameters. Serially collected nasal swabs were assayed for CWD prion seeding activity using iron oxide magnetic extraction and real-time quaking-induced conversion (IOME RT-QuIC). These findings were correlated with the results from longitudinal tonsil biopsies, terminal tissues and PRNP genotype. We detected nasal prion shedding 3–16 months after the first positive tonsil biopsy in ten of the 18 deer; detectable shedding persisted thereafter in nine of the ten animals. Surprisingly, nasal swabs were negative in eight deer, even though all were CWD-infected as determined by tonsil biopsies and terminal tissue assays. Nasal shedding was detected more often in deer that were homozygous for glycine at codon 96, and those that were near or demonstrating symptoms of clinical disease shed earlier and more frequently, irrespective of prion exposure dose. The results of this study demonstrate nasal shedding of CWD prions that can be detected using minimally invasive nasal swab sampling and RT-QuIC analysis.
ICTV Virus Taxonomy Profile: Yadokariviridae 2023
Authors: Sato Yukiyo , Das Subha , Velasco Leonardo , Turina Massimo , Osaki Hideki , Kotta-Loizou Ioly , Coutts Robert H. A. , Kondo Hideki , Sabanadzovic Sead , Suzuki Nobuhiro ,   ICTV Report Consortium
Published: January 2023

The family Yadokariviridae, with the genera Alphayadokarivirus and Betayadokarivirus, includes capsidless non-segmented positive-sense (+) RNA viruses that hijack capsids from phylogenetically distant double-stranded RNA viruses. Yadokarivirids likely replicate inside the hijacked heterocapsids using their own RNA-directed RNA polymerase, mimicking dsRNA viruses despite their phylogenetic placement in a (+) RNA virus lineage. Yadokarivirids can have negative or positive impacts on their host fungi, through interactions with the capsid donor dsRNA viruses. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) report on the family Yadokariviridae, which is available at ictv.global/report/yadokariviridae.
Leveraging comparative genomics to uncover alien genes in bacterial genomes
Authors: Sengupta Soham , Azad Rajeev K.
Published: January 2023

A significant challenge in bacterial genomics is to catalogue genes acquired through the evolutionary process of horizontal gene transfer (HGT). Both comparative genomics and sequence composition-based methods have often been invoked to quantify horizontally acquired genes in bacterial genomes. Comparative genomics methods rely on completely sequenced genomes and therefore the confidence in their predictions increases as the databases become more enriched in completely sequenced genomes. Recent developments including in microbial genome sequencing call for reassessment of alien genes based on information-rich resources currently available. We revisited the comparative genomics approach and developed a new algorithm for alien gene detection. Our algorithm compared favourably with the existing comparative genomics-based methods and is capable of detecting both recent and ancient transfers. It can be used as a standalone tool or in concert with other complementary algorithms for comprehensively cataloguing alien genes in bacterial genomes.
COVID-19 in Pakistan: A national analysis of five pandemic waves
Authors: Ahmad Taimoor , Abdullah Mujahid , Mueed Abdul , Sultan Faisal , Khan Ayesha , Khan Adnan Ahmad
Published: January 2023

Objectives

The COVID-19 pandemic showed distinct waves where cases ebbed and flowed. While each country had slight, nuanced differences, lessons from each wave with country-specific details provides important lessons for prevention, understanding medical outcomes and the role of vaccines. This paper compares key characteristics from the five different COVID-19 waves in Pakistan.

Methods

We used specific criteria to define COVID-19 waves, and key variables such as COVID-19 tests, cases, and deaths with their rates of change to the peak and then to the trough were used to draw descriptive comparisons. Additionally, a linear regression model estimated daily new COVID-19 deaths in Pakistan.

Results

Pakistan saw five distinct waves, each of which displayed the typical topology of a complete infectious disease epidemic. The time from wave-start to peak became progressively shorter, and from wave-peak to trough, progressively longer. Each wave appears to also be getting shorter, except for wave 4, which lasted longer than wave 3. A one percent increase in vaccinations increased daily new COVID-19 deaths by 0.10% (95% CI: 0.01, 0.20) in wave 4 and decreased deaths by 0.38% (95% CI: -0.67, -0.08) in wave 5.

Conclusion

Each wave displayed distinct characteristics that must be interpreted in the context of the level of response and the variant driving the epidemic. Key indicators suggest that COVID-19 preventive measures kept pace with the disease. Waves 1 and 2 were mainly about prevention and learning how to clinically manage patients. Vaccination started late during Wave 3 and its impact became apparent on hospitalizations and deaths in Wave 5. The impact of highly virulent strains Alpha/B1.1.7 and Delta/B.1.617.2 variants during Wave 3 and milder but more infectious Omicron/BA.5.2.1.7 are apparent.
Carpal tunnel syndrome with shoulder symptoms; is it a different entity? A prospective cohort study comparing recovery patterns following decompression
Authors: Ekanayake G N S , Manilgama S R
Published: January 2023

Introduction

Carpal tunnel syndrome (CTS) may present with atypical proximal symptoms other than hand symptoms. Among proximal symptoms, shoulder symptoms are most distant to the site of compression and leads to a battery of investigations to exclude other pathologies. The recovery patterns of proximal symptoms have not been studied following carpal tunnel decompression.

Method

A prospective cohort study was conducted to compare the recovery patterns between subgroup-A; CTS patients (n=55) with shoulder symptoms, with subgroup-B; patients (n=55) without shoulder symptoms. A pre-tested questionnaire was administered prior and after the surgery and information was gathered on day-7, day-14, and day-21.

Results

Of 110 patients, 81.8% were females. The mean age(±SD) of the total population was 49.2(±10.6), that of subgroup-A was 48.7(±10.3), and subgroup-B was 49.7(±11) years. They were predominantly right-handed (82.7%), 73% had their dominant hand affected while 74.5% were affected bilaterally at presentation. All had hand symptoms: numbness in 94.5%, pain in 85.4%, tingling of hand in 66.3% and all-three symptoms in 57.2%. In subgroup-A, pain was the predominant shoulder symptom which appeared before hand symptoms in 34.5%, after in 47.3% and simultaneously in 18.2%. It was aching-type in 91%. The pain radiated proximally (neck and scapula) in 61.8% and to the arm in 81.8%.

The recovery rates (RR) of hand symptoms following decompression on day-7 were 41.8% in subgroup-A and 40.0% in subgroup-B. RR of hand symptoms in subgroup-A and subgroup-B on day-14 were 72.7% and 70.9%, while on day-21 were 83.6% and 85.5% respectively. RR of shoulder symptoms in subgroup-A were 38.2% on day-7, 65.4% on day-14, and 78.2% on day-21.

Conclusion

Near identical RR of hand and shoulder symptoms were seen between the two subgroups after decompression, which indicates CTS with shoulder symptoms is not a different entity.
A quasi-experimental study to compare effectiveness of a breastfeeding arm sling with normal breastfeeding cross-cradle hold position
Authors: Disorntatiwat Pornsri , Steen Mary , Liblub Sudjit
Published: January 2023

Breastfeeding has many benefits for the newborn and mother therefore, the World Health Organization guidelines recommend exclusive breastfeeding for the first 6 months, with continued breastfeeding for up to two years. However, exclusive breastfeeding rates in the first 6 months in Thailand were reported to be approximately, 14% in 2019. Research has highlighted that many mothers’ have a lack of belief in their ability to breastfeed, and some physical conditions, such as tiredness and difficulty continually holding their baby in a comfortable position. Additionally, first-time breastfeeding can contribute to mothers having difficulties breastfeeding during the early postnatal period. Therefore, the Arm sling innovation (device) has been designed to provide support and comfort whilst holding the newborn. This study compared the effectiveness of the breastfeeding arm sling innovation to support breastfeeding in cross-cradle hold position and normal cross-cradle hold position breastfeeding in first-time mothers. A quasi-experimental pretest-posttest research design was used to evaluate the effectiveness of breastfeeding before and after the intervention among first-time mothers in the postnatal unit, at Ramathibodi hospital, Thailand. A total of 46 postpartum mothers participated in the study. The results showed that the effectiveness of breastfeeding reported by mothers between using a normal cross-cradle hold position and using breastfeeding arm sling innovation was statistically significantly different (t = 4.32, P < 0.001) with helping to hold the baby securely without slipping (t=5.68, p<0.001) and mothers can continue to breastfeed (t=2.09, p <0.001). Majority of mothers were satisfied with the support of using the breastfeeding arm sling innovation design. The breastfeeding arm sling innovation contributes to the effectiveness of breastfeeding by assisting and supporting the mother and baby’s position to breastfeed more comfortably, thus assisting first-time mothers to feel comfortable, confident, and able to continue breastfeeding.
Rapid PTEFb-dependent transcriptional reorganization underpins the glioma adaptive response to radiotherapy
Authors: Walker Faye M. , Sobral Lays Martin , Danis Etienne , Sanford Bridget , Balakrishnan Ilango , Wang Dong , Pierce Angela , Karam Sana D. , Serkova Natalie J. , Foreman Nicholas K. , Venkataraman Sujatha , Dowell Robin , Vibhakar Rajeev , Dahl Nathan A.
Published: January 2023

Abstract

Dynamic regulation of gene expression is fundamental for cellular adaptation to exogenous stressors. PTEFb-mediated pause-release of RNA polymerase II (Pol II) is a conserved regulatory mechanism for synchronous transcriptional induction in response to heat shock, but this pro-survival role has not been examined in the applied context of cancer therapy. Using model systems of pediatric high-grade glioma, we show that rapid genome-wide reorganization of active chromatin facilitates PTEFb-mediated nascent transcriptional induction within hours of exposure to therapeutic ionizing radiation. Concurrent inhibition of PTEFb disrupts this chromatin reorganization and blunts transcriptional induction, abrogating key adaptive programs such as DNA damage repair and cell cycle regulation. This combination demonstrates a potent, synergistic therapeutic potential agnostic of glioma subtype, leading to a marked induction of tumor cell apoptosis and prolongation of xenograft survival. These studies reveal a central role for PTEFb underpinning the early adaptive response to radiotherapy, opening new avenues for combinatorial treatment in these lethal malignancies.
Identification of Immune-Related Candidate Biomarkers in Plasma of Patients with Sporadic Vestibular Schwannoma
Authors: Vasilijic Sasa , Atai Nadia A. , Hyakusoku Hiroshi , Worthington Steven , Ren Yin , Sagers Jessica E. , Sahin Mehmet I , Fujita Takeshi , Landegger Lukas D. , Lewis Richard , Welling D. Bradley , Stankovic Konstantina M.
Published: January 2023

Vestibular schwannoma (VS) is intracranial tumor arising from neoplastic Schwann cells, causing hearing loss in about 95% of patients. The traditional belief that hearing deficit is caused by physical expansion of the VS, compressing the auditory nerve, does not explain the common clinical finding that patients with small tumors can have profound hearing loss, suggesting that tumor-secreted factors could influence hearing ability in VS patients. Here, we conducted profiling of patients’ plasma for 67 immune-related factors on a large cohort of VS patients (N>120) and identified candidate biomarkers associated with tumor growth (IL-16 and S100B) and hearing (MDC). We identified the 7-biomarker panel composed of MCP-3, BLC, S100B, FGF-2, MMP-14, eotaxin, and TWEAK that showed outstanding discriminatory ability for VS. These findings revealed possible therapeutic targets for VS-induced hearing loss and provided a unique diagnostic tool that may predict hearing change and tumor growth in VS patients and may help inform the ideal timing of tumor resection to preserve hearing.

Teaser

Profiling of plasma in vestibular schwannoma patients revealed biomarkers that could predict hearing change and tumor growth.
An antagonism between Spinophilin and Syd-1 operates upstream of memory-promoting presynaptic long-term plasticity
Authors: Ramesh Niraja , Escher Marc , Turrel Oriane , Lützkendorf Janine , Matkovic Tanja , Liu Fan , Sigrist Stephan J.
Published: January 2023

We still face fundamental gaps in understanding how molecular plastic changes of synapses intersect with circuit operation to define behavioral states. Here we show that an antagonism between two conserved regulatory proteins, Spinophilin (Spn) and Syd-1, controls presynaptic long-term plasticity and the maintenance of olfactory memories inDrosophila. WhileSpnmutants could not trigger nanoscopic active zone remodeling under homeostatic challenge and failed to stably potentiate neurotransmitter release, concomitant reduction of Syd-1 rescued all these deficits. The Spn/Syd-1 antagonism converged on active zone close F-actin, and genetic or acute pharmacological depolymerization of F-actin rescued theSpndeficits by allowing access to synaptic vesicle release sites. Within the intrinsic mushroom body neurons, the Spn/Syd-1 antagonism specifically controlled olfactory memory stabilization but not initial learning. Thus, this evolutionarily conserved protein complex controls behaviorally relevant presynaptic long-term plasticity, also observed in the mammalian brain but still enigmatic concerning its molecular mechanisms and behavioral relevance.
Molecular Jackhammers Eradicate Cancer Cells by Vibronic-Driven Action
Authors: Ayala-Orozco Ciceron , Galvez-Aranda Diego , Corona Arnoldo , Seminario Jorge M. , Rangel Roberto , Myers Jeffrey N. , Tour James M.
Published: January 2023

Through the actuation of vibronic modes in cell-membrane-associated aminocyanines, a new type of molecular mechanical action can be exploited to rapidly kill cells by necrosis. This is done using near-infrared light, a low energy source hitherto thought to be insufficient to permit molecular mechanical disruption of a cell membrane. Vibronic-driven action (VDA) is distinct from both photodynamic therapy and photothermal therapy in that the VDA mechanical effect on the cell membrane is not retarded by high doses of inhibitors of reactive oxygen species (ROS), and VDA does not itself induce an increase in the temperature of the media; it is also unaffected by cooling the media to 2 °C. The picosecond concerted whole-molecule-vibrations of VDA-induced mechanical disruption can be done with very low concentrations (500 nM) of the aminocyanines or low doses of light (12 Jcm-2, 80 mWcm-2for 2.5 min) to causein vitronecrotic cell death in >99% of human melanoma cells. The effect is also studiedin vivoin murine B16-F10 and human A375 melanoma in mice, underscoring the high efficiency of this approach, achieving a survival rate of 60% at day 120, and 50% of the mice becoming tumor free. The molecules that destroy cell membranes through VDA are termed molecular jackhammers (MJH) because they undergo concerted whole-molecule vibrations. Different than traditional chemotherapy, it is unlikely that a cell could develop a resistance to molecular mechanical forces, thereby providing a new modality for inducing cancer cell death.
A deep learning approach for the discovery of tumor-targeting small organic ligands from DNA-Encoded Chemical Libraries
Authors: Torng Wen , Biancofiore Ilaria , Oehler Sebastian , Xu Jin , Xu Jessica , Watson Ian , Masina Brenno , Prati Luca , Favalli Nicholas , Bassi Gabriele , Neri Dario , Cazzamalli Samuele , Feng Jianwen A.
Published: January 2023

DNA-Encoded Chemical Libraries (DELs) emerged as efficient and cost-effective ligand discovery tools, which enable the generation of protein-ligand interaction data of unprecedented size. In this article, we present an approach that combines DEL screening and instance-level deep learning modeling to identify tumor-targeting ligands against Carbonic Anhydrase IX (CAIX), a clinically validated marker of hypoxia and clear cell Renal Cell Carcinoma. We present a new ligand identification and HIT-to-LEAD strategy driven by Machine Learning (ML) models trained on DELs, which expand the scope of DEL-derived chemical motifs. CAIX screening datasets obtained from three different DELs were used to train ML models for generating novel HITs, dissimilar to elements present in the original DELs. Out of the 152 novel potential HITs that were identified with our approach and screened in anin vitroenzymatic inhibition assay, 70% displayed submicromolar activities (IC50< 1 μM). Based on the first HIT set, the model was further used to prioritize and generate LEAD compounds with nanomolar affinity forin vivotumor-targeting applications. Three LEAD candidates showed accumulation on the surface of CAIX-expressing tumor cells in cellular binding assays. The best compound displayedin vitroKDof 5.7 nM and selectively targeted tumors in mice bearing human Renal Cell Carcinoma lesions. Our results demonstrate the synergy between DEL and machine learning for the identification of novel HITs and for the successful translation of LEAD candidates forin vivotargeting applications.

Graphical Abstracts
adgrl3.1-deficient zebrafish show noradrenaline-mediated externalizing behaviors, and altered expression of externalizing disorder-candidate genes, suggesting functional targets for treatment
Authors: Fontana Barbara D. , Reichmann Florian , Tilley Ceinwen A. , Lavlou Perrine , Shkumatava Alena , Alnassar Nancy , Hillman Courtney , Karlsson Karl Ægir , Norton William H.J. , Parker Matthew O.
Published: January 2023

Externalising disorders (ED) are a cause of concern for public health, and their high heritability make genetic risk factors a priority for research. Adhesion G Protein-Coupled Receptor L3 (ADGRL3) is strongly linked to several EDs, and loss-of-function models have shown impacts of this gene on several core ED-related behaviors. For example,adgrl3.1-/-zebrafish show high levels of hyperactivity. However, our understanding of the mechanisms by which this gene influences behavior is incomplete. Here we characterized, for the first time, externalizing behavioral phenotypes ofadgrl3.1-/-zebrafish and found them to be highly impulsive, show boldness in a novel environment, have attentional deficits, and show high levels of hyperactivity. All of these phenotypes were rescued by atomoxetine, demonstrating noradrenergic mediation of the externalizing effects ofadgrl3.1. Transcriptomic analyses of the brains ofadgrl3.1-/-vs wild type fish revealed several differentially expressed genes and enriched gene clusters that were independent of noradrenergic manipulation. This suggests new putative functional pathways underlying ED-related behaviors, and potential targets for the treatment of ED.
Lifelong olfactory deprivation-dependent cortical reorganization restricted to orbitofrontal cortex
Authors: Peter Moa G. , Darki Fahimeh , Thunell Evelina , Mårtensson Gustav , Postma Elbrich M. , Boesveldt Sanne , Westman Eric , Lundström Johan N.
Published: January 2023

Prolonged sensory deprivation has repeatedly been linked to cortical reorganization. We recently demonstrated that individuals with congenital anosmia (CA, complete olfactory deprivation since birth) have seemingly normal morphology in piriform (olfactory) cortex despite profound morphological deviations in the orbitofrontal cortex (OFC), a finding contradictory to both the known effects of blindness on visual cortex and to the sparse literature on brain morphology in anosmia. To establish whether these unexpected findings reflect the true brain morphology in CA, we first performed a direct replication of our previous study. Individuals with CA (n=30) were compared to age and sex matched controls (n=30) using voxel- and surface-based morphometry. The replication results were near identical to the original study: bilateral clusters of group differences in the OFC, including CA atrophy around the olfactory sulci and volume increases in the medial orbital gyri. Importantly, no group differences in piriform cortex were detected. Subsequently, to assess any subtle patterns of group differences not detectable by our mass-univariate analysis, we explored the data from a multivariate perspective. Combining the newly collected data with data from the replicated study (CA=49, Control=49) we performed support vector machine classification based on gray matter volume. In line with the mass-univariate analyses, the multivariate analysis could accurately differentiate between the groups in bilateral OFC (75-96% accuracy), whereas the classification accuracy in piriform cortex was at chance level. Our results suggest that despite lifelong olfactory deprivation, piriform (olfactory) cortex is morphologically unaltered and the morphological deviations in CA are confined to the OFC.
Strain tracking with uncertainty quantification
Authors: Kim Younhun , Worby Colin J. , Acharya Sawal , van Dijk Lucas R. , Alfonsetti Daniel , Gromko Zackary , Azimzadeh Philippe , Dodson Karen , Gerber Georg , Hultgren Scott , Earl Ashlee M. , Berger Bonnie , Gibson Travis E.
Published: January 2023

The ability to detect and quantify microbiota over time has a plethora of clinical, basic science, and public health applications. One of the primary means of tracking microbiota is through sequencing technologies. When the microorganism of interest is well characterized or knowna priori, targeted sequencing is often used. In many applications, however, untargeted bulk (shotgun) sequencing is more appropriate; for instance, the tracking of infection transmission events and nucleotide variants across multiple genomic loci, or studying the role of multiple genes in a particular phenotype. Given these applications, and the observation that pathogens (e.g.Clostridioides difficile, Escherichia coli, Salmonella enterica) and other taxa of interest can reside at low relative abundance in the gastrointestinal tract, there is a critical need for algorithms that accurately track low-abundance taxa with strain level resolution. Here we present a sequence quality- and time-aware model,ChronoStrain, that introduces uncertainty quantification to gauge low-abundance species and significantly outperforms the current state-of-the-art on both real and synthetic data. ChronoStrain leverages sequences’ quality scores and the samples’ temporal information to produce a probability distribution over abundance trajectories for each strain tracked in the model. We demonstrate Chronostrain’s improved performance in capturing post-antibioticEscherichia colistrain blooms among women with recurrent urinary tract infections (UTIs) from the UTI Microbiome (UMB) Project. Other strain tracking models on the same data either show inconsistent temporal colonization or can only track consistently using very coarse groupings. In contrast, our probabilistic outputs can reveal the relationship between low-confidence strains present in the sample that cannot be reliably assigned a single reference label (either due to poor coverage or novelty) while simultaneously calling high-confidence strains that can be unambiguously assigned a label. We also analyze samples from the Early Life Microbiota Colonisation (ELMC) Study demonstrating the algorithm’s ability to correctly identifyEnterococcus faecalisstrains using paired sample isolates as validation.
Adjustments to the reference dataset design improves cell type label transfer
Authors: Mölbert Carla , Haghverdi Laleh
Published: January 2023

The transfer of cell type labels from prior annotated (reference) to newly collected data is an important task in single-cell data analysis. As the number of publicly available annotated datasets which can be used as a reference, as well as the number of computational methods for cell type label transfer are constantly growing, rationals to understand and decide which reference design and which method to use for a particular query dataset is needed. Here, we benchmark a set of five popular cell type annotation methods, study the performance on different cell types and highlight the importance of the design of the reference data (number of cell samples for each cell type, inclusion of multiple datasets in one reference, gene set selection, etc.) for more reliable predictions.
Aminobenzoic acid derivatives obstruct induced fit in the catalytic center of the ribosome
Authors: Majumdar Chandrima , Walker Joshua A. , Francis Matthew B. , Schepartz Alanna , Cate Jamie H. D.
Published: January 2023

TheEscherichia coliribosome can incorporate a variety of non-l-α-amino acid monomers into polypeptide chains, but with poor efficiency. Although these monomers span a diverse set of compounds, there exists no high-resolution structural information regarding their positioning within the catalytic center of the ribosome, the peptidyl transferase center (PTC). Thus, details regarding the mechanism of amide bond formation and the structural basis for differences and defects in incorporation efficiency remain unknown. Within a set of three aminobenzoic acid derivatives–3-aminopyridine-4-carboxylic acid (Apy),ortho-aminobenzoic acid (oABZ), andmeta-aminobenzoic acid (mABZ)–the ribosome incorporates Apy into polypeptide chains with the highest efficiency, followed byoABZ and thenmABZ, a trend that does not track with the nucleophilicity of the reactive amines. Here, we report high resolution cryo-EM structures of the ribosome with these three aminobenzoic acid derivatives charged on tRNA bound in the aminoacyl-tRNA site (A site). These structures reveal how the aromatic ring of each monomer sterically blocks positioning of nucleotide U2506, thereby preventing rearrangement of nucleotide U2585 and the resulting induced fit in the PTC required for efficient amide bond formation. They also reveal disruptions to the “proton wire” responsible for facilitating formation and breakdown of the tetrahedral intermediate. Together, the cryo-EM structures reported here provide a clear rationale for differences in reactivity of aminobenzoic acid derivatives relative tol-α-amino acids and each other, and point to stereochemical constraints on the size and geometry of non-proteinogenic monomers that can be accepted efficiently by wild-type ribosomes.
A supervised Bayesian factor model for the identification of multi-omics signatures
Authors: Gygi Jeremy P. , Konstorum Anna , Pawar Shrikant , Aron Edel , Kleinstein Steven H. , Guan Leying
Published: January 2023

Motivation

Predictive biological signatures provide utility as biomarkers for disease diagnosis and prognosis, as well as prediction of responses to vaccination or therapy. These signatures are identified from high-throughput profiling assays through a combination of dimensionality reduction and machine learning techniques. The genes, proteins, metabolites, and other biological analytes that compose signatures also generate hypotheses on the underlying mechanisms driving biological responses, thus improving biological understanding. Dimensionality reduction is a critical step in signature discovery to address the large number of analytes in omics datasets, especially for multi-omics profiling studies with tens of thousands of measurements. Latent factor models, which can account for the structural heterogeneity across diverse assays, effectively integrate multi-omics data and reduce dimensionality to a small number of factors that capture correlations and associations among measurements. These factors provide biologically interpretable features for predictive modeling. However, multi-omics integration and predictive modeling are generally performed independently in sequential steps, leading to suboptimal factor construction. Combining these steps can yield better multi-omics signatures that are more predictive while still being biologically meaningful.

Results

We developed a supervised variational Bayesian factor model that extracts multi-omics signatures from high-throughput profiling datasets that can span multiple data types. Signature-based multiPle-omics intEgration via lAtent factoRs (SPEAR) adaptively determines factor rank, emphasis on factor structure, data relevance and feature sparsity. The method improves the reconstruction of underlying factors in synthetic examples and prediction accuracy of COVID-19 severity and breast cancer tumor subtypes.

Availability

SPEAR is a publicly available R-package hosted athttps://bitbucket.org/kleinstein/SPEAR.

Contact

jeremy.gygi@yale.edu;leying.guan@yale.edu
Assessment of Treatment-Specific Tethering Survival Bias for the Juvenile blue crabCallinectes Sapidusin a Simulated Salt Marsh
Authors: Miller Cole R. , Hyman A. Challen , Shi Daniel , Lipcius Romuald N.
Published: January 2023

The blue crab (Callinectes sapidus) is ecologically and economically important in Chesapeake Bay. Nursery habitats, such as seagrass beds, disproportionately contribute individuals to the adult segment of populations.Spartina alterniflorasalt marshes are intertidal nursery habitats which may serve as a refuge from predation for juvenile blue crabs. However, the effects of various characteristics of salt marshes on nursery metrics, such as survival, have not been quantified. Comparisons of juvenile survival between salt marshes and other habitats often employ tethering to assess survival. Although experimental bias when tethering juvenile prey is well recognized, the potential for habitat-specific bias in salt marshes has not been experimentally tested. Using mesocosm experiments, we tested if tethering in simulated salt marsh habitats produces a habitat-specific bias. Juvenile crabs were randomly tethered and un-tethered in mesocosms at varying simulated shoot densities. Tethering reduced survival, and its effect was not habitat specific, irrespective of shoot density, as evidenced by a non-significant interaction effect between tethering treatment and habitat. Thus, tethering juvenile blue crabs in salt marsh habitat did not produce treatment-specific bias relative to unvegetated habitat across a range of shoot densities and survival of tethered and untethered crabs was positively related to shoot density. These findings indicate that tethering is a useful method for assessing survival in salt marshes, as with other nursery habitats including seagrass beds, algae and unstructured sand.
An intrinsically interpretable neural network architecture for sequence to function learning
Authors: Balci Ali Tugrul , Ebeid Mark Maher , Benos Panayiotis V , Kostka Dennis , Chikina Maria
Published: January 2023

Motivation: Sequence-based deep learning approaches have been shown to predict a multitude of functional genomic readouts, including regions of open chromatin and RNA expression of genes. However, a major limitation of current methods is that model interpretation relies on computationally demanding post hoc analyses, and even then, one can often not explain the internal mechanics of highly parameterized models. Here, we introduce a deep learning architecture called tiSFM (totally interpretable sequence to function model). tiSFM improves upon the performance of standard multi-layer convolutional models while using fewer parameters. Additionally, while tiSFM is itself technically a multi-layer neural network, internal model parameters are intrinsically interpretable in terms of relevant sequence motifs. Results: We analyze published open chromatin measurements across hematopoietic lineage cell-types and demonstrate that tiSFM outperforms a state-of-the-art convolutional neural network model custom-tailored to this dataset. We also show that it correctly identifies context specific activities of transcription factors with known roles in hematopoietic differentiation, including Pax5 and Ebf1 for B-cells, and Rorc for innate lymphoid cells. tiSFM's model parameters have biologically meaningful interpretations, and we show the utility of our approach on a complex task of predicting the change in epigenetic state as a function of developmental transition. Availability and implementation : The source code, including scripts for the analysis of key findings, can be found at https://github.com/boooooogey/ATAConv, implemented in Python.
Activated Sludge Microbial Community Assembly: The Role of Influent Microbial Community Immigration
Authors: Gibson Claire , Jauffur Shameem , Guo Bing , Frigon Dominic
Published: January 2023

Wastewater treatment plants (WWTPs) are host to diverse microbial communities and receive a constant influx of microbes from influent wastewater, however the impact of immigrants on the structure and activities of the activated sludge (AS) microbial community remains unclear. To gain insight on this phenomenon known as perpetual community coalescence, the current study utilised controlled manipulative experiments that decoupled the influent wastewater composition from the microbial populations to reveal the fundamental mechanisms involved in immigration between sewers and AS-WWTP. The immigration dynamics of heterotrophs were analysed by harvesting wastewater biomass solids from 3 different sewer systems and adding to synthetic wastewater. Immigrating influent populations were observed to contribute up to 25 % of the sequencing reads in the AS. By modelling the net growth rate of taxa, it was revealed that immigrants primarily exhibited low or negative net growth rates. By developing a protocol to reproducibly grow AS-WWTP communities in the lab, we have laid down the foundational principals for the testing of operational factors creating community variations with low noise and appropriate replication. Understanding the processes that drive microbial community diversity and assembly is a key question in microbial ecology. In the future, this knowledge can be used to manipulate the structure of microbial communities and improve system performance in WWTPs.

Importance

In biological wastewater treatment processes, the microbial community composition is essential in the performance and stability of the system. To allow future process optimisation to meet new treatment goals, we need a better understanding of factors influencing the microbial community assembly in WWTPs. This study developed a reproducible protocol to investigates the impact of influent immigration (or perpetual coalescence of the sewer and activated sludge communities) with appropriate reproducibility and controls. We demonstrate herein that influent immigration contributed up to 25 % of the sequencing reads in the activated sludge under the studied conditions, highlighting the need to consider this process in future WWTP modelling and design.
Patterns of within-host spread ofChlamydia trachomatisbetween vagina, endocervix and rectum revealed by comparative genomic analysis
Authors: Joseph Sandeep J. , Bommana Sankhya , Ziklo Noa , Kama Mike , Dean Deborah , Read Timothy D.
Published: January 2023

Chlamydia trachomatis, a gram-negative obligate intracellular bacterium, commonly causes sexually transmitted infections (STIs). Little is known aboutC. trachomatistransmission within the host, which is important for understanding disease epidemiology and progression. We used RNA-bait enrichment and whole-genome sequencing to compare rectal, vaginal and endocervical samples collected at the same time from 26 study participants who attended Fijian Ministry of Health and Medical Services clinics and tested positive forC. trachomatisat each anatomic site. The 78C. trachomatisgenomes from participants were from two major clades of theC. trachomatisphylogeny (the “prevalent urogenital and anorecta”l clade and “non-prevalent urogenital and anorectal” clade). For 21 participants, genome sequences were almost identical in each anatomic site. For the other five participants, two distinctC. trachomatisstrains were present in different sites; in two cases, the vaginal sample was a mixture of strains. The absence of large numbers of fixed SNPs betweenC. trachomatisstrains within many of the participants could indicate recent acquisition of infection prior to the clinic visit without sufficient time to accumulate significant variation in the different body sites. This model suggests that manyC. trachomatisinfections may be resolved relatively quickly in the Fijian population, possibly reflecting common prescription or over-the-counter antibiotics usage.

Importance

Chlamydia trachomatisis a bacterial pathogen that causes millions of sexually transmitted infections (STIs) annually across the globe. BecauseC. trachomatislives inside human cells, it has historically been hard to study. We know little about how the bacterium spreads between body sites. Here, samples from 26 study participants who had simultaneous infections in their vagina, rectum and endocervix were genetically analyzed using an improved method to extractC. trachomatisDNA directly from clinical samples for genome sequencing. By analyzing patterns of mutations in the genomes, we found that 21 participants shared very similarC. trachomatisstrains in all three anatomic sites, suggesting recent infection and spread. For five participants twoC. trachomatisstrains were evident, indicating multiple infections. This study is significant in that improved enrichment methods for genome sequencing provides robust data to genetically trace patterns ofC. trachomatisinfection and transmission within an individual for epidemiologic and pathogenesis interrogations.
CRaTER enrichment for on-target gene-editing enables generation of variant libraries in hiPSCs
Authors: Friedman Clayton E. , Fayer Shawn , Pendyala Sriram , Chien Wei-Ming , Tran Linda , Chao Leslie , Mckinstry Ashley , Karbassi Elaheh , Fenix Aidan M. , Loiben Alexander , Murry Charles E. , Starita Lea M. , Fowler Douglas M. , Yang Kai-Chun
Published: January 2023

Standard transgenic cell line generation requires screening 100-1000s of colonies to isolate correctly edited cells. We describeCRISPRaOn-TargetEditingRetrieval (CRaTER) which enriches for cells with on-target knock-in of a cDNA-fluorescent reporter transgene by transient activation of the targeted locus followed by flow sorting to recover edited cells. We show CRaTER recovers rare cells with heterozygous, biallelic-editing of the transcriptionally-inactiveMYH7locus in human induced pluripotent stem cells (hiPSCs), enriching on average 25-fold compared to standard antibiotic selection. We leveraged CRaTER to enrich for heterozygous knock-in of a library of single nucleotide variants (SNVs) inMYH7, a gene in which missense mutations cause cardiomyopathies, and recovered hiPSCs with 113 differentMYH7SNVs. We differentiated these hiPSCs to cardiomyocytes and show MYH7 fusion proteins can localize as expected. Thus, CRaTER substantially reduces screening required for isolation of gene-edited cells, enabling generation of transgenic cell lines at unprecedented scale.