bluuebunny/crossref_metadata_2025 huggingface dataset:
Modified adaptation of the twist-and-out technique for intraocular lens exchange
Authors: Duncan Nicole B. , Micheletti J. Morgan
Published: August 2022

Many methods can be used to explant an intraocular lens (IOL) after prior cataract surgery. Here, we describe a modified approach to the twist-and-out technique for IOL removal. The IOL is dissected and brought into the anterior chamber (AC), where 1 haptic is externalized. The adaptation in this technique occurs next; an additional paracentesis is made 180 degrees away from an adjacent side port, and the shaft of a 25-gauge cannula is threaded across the AC to connect these incisions. This maneuver frees both hands to use forceps within the incision, grasp the IOL, and rotate it around the forceps. The use of both hands allows for a smaller, more controlled movement than the original 1-handed pronation. The cannula shaft aids in twisting the IOL tightly around the forceps while protecting the corneal endothelium. The forceps-lens complex is then withdrawn, extracting the IOL whole with 1 efficient movement.
Long-Term Audiometric Outcomes of a Self-Crimping Stapes Prosthesis With CO2 Laser Stapedotomy
Authors: Shoman Nael M.
Published: August 2022

Objective

To evaluate our experience with a self-crimping stapes prosthesis.

Study Design

Retrospective case review.

Setting

Tertiary referral center.

Patients

All patients diagnosed with otosclerosis who underwent surgery between June 2013 and June 2020. Inclusion criteria were 18 years or older, isolated stapes ankylosis, and at least 1 year of postoperative audiologic data.

Intervention(s)

CO2 laser stapedotomy undertaken by the same surgeon using the same CO2 laser stapedotomy technique and the same prosthesis.

Main Outcome Measure(s)

Preoperative and postoperative audiologic data including air-bone gap (ABG) measurements, average speech discrimination score and pure-tone averages (PTAs). Postoperative hearing assessments were performed at 3 weeks, 3 months, 6 months, 1 year, and annually thereafter.

Results

Two hundred fourteen patients were included in the study, of whom 17 had bilateral sequential surgery for a total of 231 ears. Mean preoperative air conduction-PTA was 58.8 dB and mean preoperative bone conduction-PTA 24.2 dB, a preoperative ABG of 34.6 dB. One year postoperatively, mean air conduction-PTA improved to 31.2 dB (p < 0.0001). ABG showed a significant improvement from 34.6 to 5.5 dB (p < 0.0001). Closure of the ABG to within 10 dB was achieved in 87% ears at 3 months, in 91% at 6 months, and in 93% at 1 year. There was no significant difference in preoperative and postoperative average speech discrimination score.

Conclusion

The current study demonstrates favorable audiologic outcomes in a large cohort of patients using a self-crimping stapes prosthesis. These results were stable for up to 7 years on follow-up.
Audiometric and Surgical Outcomes of a Novel Bone-Conduction Hearing Aid
Authors: Quimby Alexandra E. , Park Jino , Brant Jason A. , Eliades Steven J. , Kaufman Hannah S. , Bigelow Douglas C. , Ruckenstein Michael J.
Published: August 2022

Objective

To report the audiometric and surgical outcomes of a series of patients having undergone implantation of a novel transcutaneous bone conduction implant (t-BCI).

Study Design

Retrospective case series.

Setting

Single academic tertiary referral center.

Patients

Adults (≥18 yr) implanted between December 1, 2019, and August 1, 2021, with audiometric data available before and after device implantation and a minimum of 4 weeks follow-up.

Interventions

Surgical t-BCI.

Main Outcome Measures

Change in aided pure tone average (PTA) after implantation. Secondary outcomes include average operative time, and adverse events.

Results

Twenty-three patients underwent implantation of the t-BCI via either a conventional or minimally invasive surgical approach. The most common indication for implantation was unilateral conductive hearing loss with a history of chronic otitis media. The mean operative time was 59 minutes. The mean preimplantation unaided air conduction PTA was 65 dB, and mean postimplantation was 27.2 dB. The mean change in PTA was 37.8 dB, which was significant (p < 0.0001). There were 30.4% of the patients that suffered from adverse events, the most common of which were pain (8.7%) and device-related complications (13%). One major adverse event occurred, involving magnet displacement that impaired device activation and required reoperation for replacement.

Conclusion

Forming the largest series of patients implanted with this t-BCI in the published literature, our data demonstrate that implantation of the device is feasible via either a traditional or minimally invasive surgical approach, with good audiometric benefit and a favorable safety profile.
A Single Gallbladder Fold Creates a Unique Visual and Temporal Pattern of Radiotracer Accumulation on Hepatobiliary Scintigraphy
Authors: Iyalomhe Osigbemhe , Rowe Steven P.
Published: August 2022

Duplication of the gallbladder represents a variant of anomalous biliary anatomy that is rarely encountered on hepatobiliary scintigraphy. We describe the case of 76-year-old man with a gallbladder fold mimicking duplication of the gallbladder or an associated choledochal cyst on scintigraphy. Correlative imaging with CT and ultrasound helped elucidate the true anatomy. This case demonstrates the type of difficult scintigraphic patterns that can arise with variant anatomy and the necessary role of cross-sectional, anatomic imaging in unraveling such situations.
Late-Term Findings of Pancreatitis on 68Ga-PSMA PET/CT in a Patient With Prostate Cancer
Authors: Tosunoğlu Zehranur , Erol Fenercioğlu Özge , Beyhan Ediz , Arslan Esra , Çermik Tevfik Fikret
Published: August 2022

The 68Ga-PSMA PET/CT imaging modality is used to evaluate biochemical recurrence, response to treatment, and staging in prostate cancer. Prostate-specific membrane antigen (PSMA) receptor activation can be seen in benign and malignant diseases as well as in many physiological tissues. Many pitfalls and artifacts have been reported when reporting 68Ga-PSMA PET/CT. In this case, diffuse moderate PSMA receptor activation in pancreatic tissue due to the previous pancreatitis is presented in 68Ga-PSMA PET/CT imaging modality that was performed for restaging of prostate cancer.
Potential Pitfall of Fluciclovine PET/CT in Castrate-Resistant Prostate Cancer With Adrenal Metastasis
Authors: Qi Jin , Nguyen Nghi C.
Published: August 2022

An 83-year-old man with castrate-resistant prostate cancer underwent an 18F-fluciclovine PET/CT scan, which was negative for local disease recurrence or locoregional lymphadenopathy, but there were multiple fluciclovine-avid bone metastases. In addition, mildly avid bilateral adrenal nodules were thought to be benign. However, on follow-up PET/CT 10 months later, while on additional therapy with enzalutamide, the bilateral nodules became mass lesions with interval decreased fluciclovine avidity. Adrenal metastases were suspected given their rapid growth, with subsequent CT-guided biopsy revealing metastatic prostate cancer without tumor necrosis. This false-negative case highlights the diagnostic challenge of fluciclovine PET in characterizing adrenal lesions.
Infection, Rejection, and the Connection
Authors: Higdon Lauren E. , Tan Jane C. , Maltzman Jonathan S.
Published: August 2022

Solid organ transplantation is a life-saving treatment for people with end-stage organ disease. Immune-mediated transplant rejection is a common complication that decreases allograft survival. Although immunosuppression is required to prevent rejection, it also increases the risk of infection. Some infections, such as cytomegalovirus and BK virus, can promote inflammatory gene expression that can further tip the balance toward rejection. BK virus and other infections can induce damage that resembles the clinical pathology of rejection, and this complicates accurate diagnosis. Moreover, T cells specific for viral infection can lead to rejection through heterologous immunity to donor antigen directly mediated by antiviral cells. Thus, viral infections and allograft rejection interact in multiple ways that are important to maintain immunologic homeostasis in solid organ transplant recipients. Better insight into this dynamic interplay will help promote long-term transplant survival.
Improving treatment outcomes for borderline personality disorder: what can we learn from biomarker studies of psychotherapy?
Authors: Marceau Ely M. , Ruocco Anthony C. , Grenyer Brin F.S.
Published: August 2022

Purpose of review

Borderline personality disorder (BPD) is a severe and common psychiatric disorder and though evidence-based psychotherapies are effective, rates of treatment nonresponse are as high as 50%. Treatment studies may benefit from interdisciplinary approaches from neuroscience and genetics research that could generate novel insights into treatment mechanisms and tailoring interventions to the individual.

Recent findings

We provide a timely update to the small but growing body of literature investigating neurobiological and epigenetic changes and using biomarkers to predict outcomes from evidence-based psychotherapies for BPD. Using a rapid review methodology, we identified eight new studies, updating our earlier 2018 systematic review. Across all studies, neuroimaging (n = 18) and genetics studies (n = 4) provide data from 735 participants diagnosed with BPD (mean sample size across studies = 33.4, range 2–115).

We report further evidence for psychotherapy-related alterations of neural activation and connectivity in regions and networks relating to executive control, emotion regulation, and self/interpersonal functioning in BPD. Emerging evidence also shows epigenetic changes following treatment. Future large-scale multisite studies may help to delineate multilevel treatment targets to inform intervention design, selection, and monitoring for the individual patient via integration of knowledge generated through clinical, neuroscience, and genetics research.
Evaluation of Transfer Learning Methods for Detecting Alzheimer’s Disease with Brain MRI
Authors: Dhinagar Nikhil J. , Thomopoulos Sophia I. , Rajagopalan Priya , Stripelis Dimitris , Ambite Jose Luis , Ver Steeg Greg , Thompson Paul M.
Published: August 2022

Deep neural networks show great promise for classifying brain diseases and making prognostic assessments based on neuroimaging data, but large, labeled training datasets are often required to achieve high predictive accuracy. Here we evaluated a range oftransfer learningor pre-training strategies to create useful MRI representations for downstream tasks that lack large amounts of training data, such as Alzheimer’s disease (AD) classification. To test our proposed pre-training strategies, we analyzed 4,098 3D T1-weighted brain MRI scans from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort and independently validated with an out-of-distribution test set of 600 scans from the Open Access Series of Imaging Studies (OASIS3) cohort for detecting AD. First, we trained 3D and 2D convolutional neural network (CNN) architectures. We tested combinations of multiple pre-training strategies based on (1) supervised, (2) contrastive learning, and (3) self-supervised learning - using pre-training data within versus outside the MRI domain. In our experiments, the 3D CNN pre-trained with contrastive learning provided the best overall results - when fine-tuned on T1-weighted scans for AD classification - outperformed the baseline by 2.8% when trained with all of the training data from ADNI. We also show test performance as a function of the training dataset size and the chosen pre-training method. Transfer learning offered significant benefits in low data regimes, with a performance boost of 7.7%. When the pre-trained model was used for AD classification, we were able to visualize an improved clustering of test subjects’ diagnostic groups, as illustrated via a uniform manifold approximation (UMAP) projection of the high-dimensional model embedding space. Further, saliency maps indicate the additional activation regions in the brain scan using pre-training, that then maximally contributed towards the final prediction score.
The kinesin motor KIF1C is a putative transporter of the exon junction complex in neuronal cells
Authors: Nagel Maike , Noß Marvin , Xu Jishu , Horn Nicola , Ueffing Marius , Boldt Karsten , Schüle Rebecca
Published: August 2022

Neurons critically depend on regulated RNA localization and tight control of spatio-temporal gene expression to maintain their morphological and functional integrity. Mutations in the kinesin motor protein gene KIF1C cause Hereditary Spastic Paraplegia, an autosomal recessive disease leading to predominant degeneration of the long axons of central motoneurons. In this study we aimed to gain insight into the molecular function of KIF1C and understand how KIF1C dysfunction contributes to motoneuron degeneration.

We used affinity proteomics in neuronally differentiated neuroblastoma cells (SH-SY5Y) to identify the protein complex associated with KIF1C in neuronal cells; candidate interactions were then validated by immunoprecipitation and mislocalization of putative KIF1C cargoes was studied by immunostainings.

We found KIF1C to interact with all core components of the exon junction complex (EJC); expression of mutant KIF1C in neuronal cells leads to loss of the typical localization distally in neurites. Instead, EJC core components accumulate in the pericentrosomal region, here co-localizing with mutant KIF1C. These findings suggest KIF1C as a neuronal transporter of the EJC. Interestingly, the binding of KIF1C to the EJC is RNA-mediated, as treatment with RNAse prior to immunoprecipitation almost completely abolishes the interaction. Silica-based solid-phase extraction of UV-crosslinked RNA-protein complexes furthermore supports direct interaction of KIF1C with RNA, as recently also demonstrated for kinesin heavy chain. Taken together, our findings are consistent with a model where KIF1C transports mRNA in an EJC-bound and therefore transcriptionally silenced state along neurites, thus providing the missing link between the EJC and mRNA localization in neurons.
MND1 and PSMC3IP control PARP inhibitor sensitivity in mitotic cells
Authors: Zelceski Anabel , Francica Paola , Lingg Lea , Mutlu Merve , Stok Colin , Liptay Martin , Alexander John , Baxter Joseph S. , Brough Rachel , Gulati Aditi , Haider Syed , Raghunandan Maya , Song Feifei , Sridhar Sandhya , Forment Josep V. , O’Connor Mark J. , Davies Barry R. , van Vugt Marcel A.T.M. , Krastev Dragomir B. , Pettitt Stephen J. , Tutt Andrew N. J. , Rottenberg Sven , Lord Christopher J.
Published: August 2022

The PSMC3IP-MND1 heterodimer promotes RAD51 and DMC1-dependent D-loop formation during meiosis in yeast and mammalian organisms. For this purpose, it catalyzes the DNA strand exchange activities of the recombinases. Interestingly, in a panel of genome-scale CRISPR-Cas9 mutagenesis and interference screens in mitotic cells, we found that depletion of either PSMC3IP or MND1 caused sensitivity to clinical Poly (ADP-Ribose) Polymerase inhibitors (PARPi). A retroviral mutagenesis screen in mitotic cells also identified PSMC3IP and MND1 as genetic determinants of ionizing radiation sensitivity. The role PSMC3IP and MND1 play in preventing PARPi sensitivity in mitotic cells appears to be independent of a previously described role in alternative lengthening of telomeres (ALT). PSMC3IP or MND1 depleted cells accumulate toxic RAD51 foci in response to DNA damage, show impaired homology-directed DNA repair, and become PARPi sensitive, even in cells lacking both BRCA1 and TP53BP1. Although replication fork reversal is also affected, the epistatic relationship between PSMC3IP-MND1 and BRCA1/BRCA2 suggests that the abrogated D-loop formation is the major cause of PARPi sensitivity. This is corroborated by the fact that a PSMC3IP p.Glu201del D-loop formation mutant associated with ovarian dysgenesis fails to reverse PARPi sensitivity. These observations suggest that meiotic proteins such as MND1 and PSMC3IP could have a greater role in mitotic cells in determining the response to therapeutic DNA damage.
Early midbrain sensorimotor pathway is involved in the timely initiation and direction of swimming in the hatchling Xenopus laevis tadpole
Authors: Larbi Michelle Christine , Messa Giulia , Jalal Helin , Koutsikou Stella
Published: August 2022

Vertebrate locomotion is heavily dependent on descending control originating in the midbrain and subsequently influencing central pattern generators in the spinal cord. However, the midbrain neuronal circuitry and its connections with other brainstem and spinal motor circuits has not been fully elucidated. Basal vertebrates with very simple nervous system, like the hatchling Xenopus laevis tadpole, have been instrumental in unravelling fundamental principles of locomotion and its suspraspinal control. Here, we use behavioral and electrophysiological approaches in combination with lesions of the midbrain to investigate its contribution to the initiation and control of the tadpole swimming in response to trunk skin stimulation. None of the midbrain lesions studied here blocked the tadpole’s sustained swim behavior following trunk skin stimulation. However, we identified that distinct midbrain lesions led to significant changes in the latency and trajectory of swimming. These changes could partly be explained by the increase in synchronous muscle contractions on the opposite sides of the tadpole’s body and permanent deflection of the tail from its normal position, respectively. Furthermore, the midbrain lesions led to significant changes in the tadpole’s ability to stop swimming when it bumps head on to solid objects. We conclude that the tadpole’s embryonic trunk skin sensorimotor pathway involves the midbrain, which harbors essential neuronal circuitry to significantly contribute to the appropriate, timely and coordinated selection and execution of locomotion, imperative to the animal’s survival.
Aspirin reprogrammes colorectal cancer cell metabolism and sensitises to glutaminase inhibition
Authors: Holt Amy K. , Najumudeen Arafath K. , Hoskin Ashley J. , Legge Danny N. , Mortensson Eleanor M.H. , Flanagan Dustin J. , Jones Nicholas , Kollareddy Madhu , Collard Tracey J. , Timms Penny , Sansom Owen J. , Williams Ann C. , Vincent Emma E.
Published: August 2022

To support proliferation and survival within a challenging microenvironment, cancer cells must reprogramme their metabolism. As such, targeting cancer cell metabolism is a promising therapeutic avenue. However, identifying tractable nodes of metabolic vulnerability in cancer cells is challenging due to their metabolic plasticity. Identification of effective treatment combinations to counter this is an active area of research. Aspirin has a well-established role in cancer prevention, particularly in colorectal cancer (CRC), although the mechanisms are not fully understood. Here, we comprehensively characterise the metabolic impact of long-term aspirin exposure (2-4mM for 52 weeks) on CRC cells. We show that aspirin regulates several enzymes and transporters of central carbon metabolism and results in a reduction in glutaminolysis and a concomitant increase in glucose metabolism, demonstrating reprogramming of nutrient utilisation. We show that aspirin causes likely compensatory changes that renders the cells sensitive to the glutaminase 1 (GLS1) inhibitor - CB-839. Of note given the clinical interest, treatment with CB-839 alone had little effect on CRC cell growth or survival. However, in combination with aspirin, CB-839 inhibited CRC cell proliferation and induced apoptosis in vitro, and importantly, reduced crypt proliferation in Apcfl/fl mice in vivo. Together, these results show that aspirin leads to significant metabolic reprogramming in colorectal cancer cells and raises the possibility that aspirin could significantly increase the efficacy of metabolic cancer therapies in CRC.
Disrupted Cerebral Peri-Microvascular Glycogen Promotes Capillary Constrictions and Aggravates Ischemia in Mice
Authors: Uruk Gokhan , Yilmaz-Ozcan Sinem , Cakir-Aktas Canan , Taskiran-Sag Aslihan , Donmez-Demir Buket , Duran Jordi , Guinovart Joan J. , Karatas-Kurşun Hulya , Dalkara Turgay , Yemisci Muge
Published: August 2022

Ischemic stroke results in sudden blood flow cessation, thus, unmet energy requirements. Although the clotted artery can be recanalized and blood flow is restored, brain perfusion may not be fully attained due to microvascular constrictions. Under glucose deprived and hypoxic conditions, glucose derived from the glycogen stored around peri-microvascular astrocyte end-feet may serve as an emergency fuel to meet the metabolic demand during acute period of ischemic stroke. To elucidate the impact of glycogen utilization on brain microcirculation, we administered glycogen phosphorylase inhibitor 1,4-dideoxy-1,4-imino-d-arabinitol (DAB) intracerebroventricularly. Transgenic mice in which glycogen synthase-1 expression was selectively knocked out in central nervous system (GYS1Nestin-KO) were also used. Both approaches caused microvascular constrictions mediated by CD13-positive pericyte contractions. When mice with disrupted glycogen utilization were subjected to MCA ischemia, pericyte-mediated microvascular constrictions and the infarct volumes were further increased compared to untreated controls or wild type littermates. Perimicrovascular glycogen depletions were highly correlated with microvascular constrictions as shown by Periodic acid Schiff (PAS) staining and immunolabeling with anti-glycogen antibodies. Imaging of regional cortical blood flow changes during ischemia disclosed severely compromised blood flow dynamics in mice with disrupted glycogen metabolism. In conclusion, disrupting glycogen utilization causes ischemic-like microvascular constrictions under non-ischemic circumstances and increases susceptibility to brain ischemia. Understanding the role of glycogen at neurogliovascular level in brain may provide novel insight to the pathophysiology of ischemic stroke and therapeutic opportunities.

Graphical Abstract
Dynamics of bacterial recombination in the human gut microbiome
Authors: Liu Zhiru , Good Benjamin H
Published: August 2022

Horizontal gene transfer is a ubiquitous force in microbial evolution. Previous studies have shown that the human gut is a hot spot for gene transfer between species, but the more subtle exchange of variation within species – collectively known as recombination – remains poorly characterized in this ecosystem. Here, we show how the genetic structure of the human gut microbiome provides a unique opportunity to measure individual recombination events from sequenced fecal samples, enabling quantitative comparisons of recombination across a diverse range of species that inhabit a common environment. By analyzing a large collection of recent recombination events in the core genomes of 29 gut commensals, we uncovered systematic heterogeneities in the rates and lengths of transferred segments, which are difficult to explain by existing models of ecological isolation or homology-dependent recombination rates. We also find that natural selection plays a role in facilitating the spread of genetic variants onto different strain backgrounds, both within individual hosts and across the broader global population. These results shed light on the dynamics ofin siturecombination, which place important constraints on the adaptability of gut microbial communities.
1,000 ancient genomes uncover 10,000 years of natural selection in Europe
Authors: Le Megan K. , Smith Olivia S. , Akbari Ali , Harpak Arbel , Reich David , Narasimhan Vagheesh M.
Published: August 2022

Ancient DNA has revolutionized our understanding of human population history. However, its potential to examine how rapid cultural evolution to new lifestyles may have driven biological adaptation has not been met, largely due to limited sample sizes. We assembled genome-wide data from 1,291 individuals from Europe over 10,000 years, providing a dataset that is large enough to resolve the timing of selection into the Neolithic, Bronze Age, and Historical periods. We identified 25 genetic loci with rapid changes in frequency during these periods, a majority of which were previously undetected. Signals specific to the Neolithic transition are associated with body weight, diet, and lipid metabolism-related phenotypes. They also include immune phenotypes, most notably a locus that confers immunity to Salmonella infection at a time when ancient Salmonella genomes have been shown to adapt to human hosts, thus providing a possible example of human-pathogen co-evolution. In the Bronze Age, selection signals are enriched near genes involved in pigmentation and immune-related traits, including at a key human protein interactor of SARS-CoV-2. Only in the Historical period do the selection candidates we detect largely mirror previously-reported signals, highlighting how the statistical power of previous studies was limited to the last few millennia. The Historical period also has multiple signals associated with vitamin D binding, providing evidence that lactase persistence may have been part of an oligogenic adaptation for efficient calcium uptake and challenging the theory that its adaptive value lies only in facilitating caloric supplementation during times of scarcity. Finally, we detect selection on complex traits in all three periods, including selection favoring variants that reduce body weight in the Neolithic. In the Historical period, we detect selection favoring variants that increase risk for cardiovascular disease plausibly reflecting selection for a more active inflammatory response that would have been adaptive in the face of increased infectious disease exposure. Our results provide an evolutionary rationale for the high prevalence of these deadly diseases in modern societies today and highlight the unique power of ancient DNA in elucidating biological change that accompanied the profound cultural transformations of recent human history.
A model predictive control strategy to regulate movements and interactions
Authors: Takagi A. , Gomi H. , Burdet E. , Koike Y.
Published: August 2022

Humans are adept at moving the arm to interact with objects and surfaces. The brain is thought to regulate motion and interactions using two different controllers, one specialized for movements and the other for force regulation. However, it remains unclear whether different control mechanisms are necessary. Here we show that the brain can employ a single high-level control strategy for both movement and interaction control. The Model Predictive Control (MPC) strategy introduced in this paper uses an internal model of the environment to plan the arm’s muscle activity whilst updating its predictions using periodic feedback. Computer simulations demonstrate MPC’s ability to produce human-like movements and after-effects in free and force field environments. It can simultaneously regulate both force and stiffness during interactions, and can accomplish motor tasks demanding transitions between motion and interaction control. Model Predictive Control promises to be an important tool to test ideas of motor control as it can handle nonlinear dynamics with changing environments and goals without having to specify the movement duration.
PrioriTree: a utility for improving phylodynamic analyses in BEAST
Authors: Gao Jiansi , May Michael R. , Rannala Bruce , Moore Brian R.
Published: August 2022

Phylodynamic methods are central to studies of the geographic and demographic history of disease outbreaks. Inference under discrete-geographic phylodynamic models—which involve many parameters that must be inferred from minimal information—is inherently sensitive to our prior beliefs about the model parameters. We present an interactive utility, PrioriTree, to help researchers identify and accommodate prior sensitivity in discrete-geographic inferences. Specifically, PrioriTree provides a suite of functions to generate input files for—and summarize output from—BEAST analyses for performing robust Bayesian inference, data-cloning analyses, and assessing the relative and absolute fit of candidate discrete-geographic (prior) models to empirical datasets.

Availability and Implementation

PrioriTree is distributed as an R package available at https://github.com/jsigao/prioritree, with a comprehensive user manual provided at https://bookdown.org/jsigao/prioritree_manual/.

Contact

jsigao@ucdavis.edu
A putative xanthine dehydrogenase protects Borrelia burgdorferi from reactive oxygen species and promotes virulence
Authors: Phelan James P. , Bourgeois Jeffrey S. , McCarthy Julie E , Hu Linden T.
Published: August 2022

Borrelia burgdorferi is a pathogenic bacterium and the causative agent of Lyme Disease. It is exposed to reactive oxygen species (ROS) in both the vertebrate and tick hosts. While some mechanisms by which B. burgdorferi ameliorates the effects of ROS exposure have been studied, there are likely many other unknown mechanisms of ROS neutralization that contribute to virulence. Here, we follow up on a three gene cluster of unknown function, BB_0554, BB_0555, and BB_0556, that our prior unbiased transposon insertional sequencing studies implicated in both ROS survival and survival in Ixodes scapularis. We confirmed these findings through genetic knockout and provide evidence that these genes are co-transcribed as an operon to produce a xanthine dehydrogenase. In agreement with these results, we found that B. burgdorferi exposure to either uric acid (a downstream product of xanthine dehydrogenase) or allopurinol (an inhibitor of xanthine dehydrogenase) could modulate sensitivity to ROS in a BB_0554-BB_0556 dependent manner. Together, this study identifies a previously uncharacterized three gene operon in B. burgdorferi as a putative xanthine dehydrogenase critical for virulence.

Importance

Borrelia burgdorferi, the causative agent of Lyme disease, is highly successful at evading host immune defenses such as reactive oxygen species, despite minimal identified defenses against oxidative stress. We identified a putative xanthine dehydrogenase that is important in survival of the organism when exposed to oxidative stress and in both its tick and murine hosts. The mechanism appears based on a previously unrecognized role of uric acid in neutralizing reactive oxygen species and highlights how B. burgdorferi can utilize its very limited metabolic capabilities in unique ways.
DNA-PAINT single-particle tracking (DNA-PAINT-SPT) enables extended single-molecule studies of membrane protein interactions
Authors: Niederauer Christian , Nguyen Chikim , Wang-Henderson Miles , Stein Johannes , Strauss Sebastian , Cumberworth Alex , Stehr Florian , Jungmann Ralf , Schwille Petra , Ganzinger Kristina A.
Published: August 2022

DNA-PAINT based single-particle tracking (DNA-PAINT-SPT) has recently significantly enhanced observation times in in vitro SPT experiments by overcoming the constraints of fluorophore photobleaching. However, with the reported implementation, only a single target can be imaged and the technique cannot be applied straight to live cell imaging. Here we report on leveraging this technique from a proof-of-principle implementation to a useful tool for the SPT community by introducing simultaneous live cell dual-colour DNA-PAINT-SPT for quantifying protein dimerisation and tracking proteins in living cell membranes, demonstrating its improved performance over single-dye SPT.
Norepinephrine enhances oligodendrocyte precursor cell calcium dynamics in the cerebral cortex during arousal
Authors: Lu Tsai-Yi , Hanumaihgari Priyanka , Hsu Eric T. , Agarwal Amit , Bergles Dwight E.
Published: August 2022

Oligodendrocytes are generated from a widely distributed population of progenitors that express neurotransmitter receptors, but the mechanisms that alter activity of these oligodendrocyte precursor cells (OPCs) in vivo have not been determined. We generated a novel line of transgenic mice to express membrane-anchored GCaMP6s in OPCs and used longitudinal two-photon microscopy to monitor their Ca2+ changes in the cerebral cortex of awake mice. OPCs exhibited high rates of spontaneous activity, consisting of focal, transient Ca2+ increases within their highly ramified processes. Unexpectedly, these events occurred independent of excitatory neuron activity, but were inhibited by anesthesia, sedative agents, and antagonists of noradrenergic signaling. These norepinephrine enhanced Ca2+ dynamics rapidly declined as with differentiation. Selective knockout of α1A adrenergic receptors in OPCs suppressed both spontaneous and locomotion-induced Ca2+ increases, indicating that OPCs are directly modulated by norepinephrine in vivo, providing a means to alter their dynamics and lineage progression during distinct brain states.
Classification of Human Chronotype Based on fMRI Network-Based Statistics
Authors: Mason Sophie L. , Junges Leandro , Woldman Wessel , Facer-Childs Elise R. , de Campos Brunno M. , Bagshaw Andrew P. , Terry John R.
Published: August 2022

Chronotype - the relationship between the internal circadian physiology of an individual and the external 24-hour light-dark cycle - is increasingly implicated in mental health and cognition. Individuals presenting with a late chronotype have an increased likelihood of developing depression, and can display reduced cognitive performance during the societal 9-5 day. However, the interplay between physiological rhythms and the brain networks that underpin cognition and mental health are not well understood. To address this issue, we use resting state fMRI collected from 16 people with an early chronotype and 22 people with a late chronotype to study if differentiable information about chronotype is embedded in functional brain networks. We develop a classifier utilising the Network Based-Statistic (NBS) methodology, using rigorous selection criteria to select t-statistic thresholds within the NBS approach. We find significant differences in functional networks measured in early and late chronotypes and describe conditions under which the classifier achieves 97.3% accuracy. Revealing differences in functional brain networks based on extreme chronotype suggests future avenues of research that may ultimately better characterise the relationship between internal physiology, external perturbations, brain networks and disease.
MARVEL: An integrated alternative splicing analysis platform for single-cell RNA sequencing data
Authors: Wen Wei Xiong , Mead Adam J , Thongjuea Supat
Published: August 2022

Alternative splicing is an important source of heterogeneity in gene expression between individual cells but remains an understudied area due to the paucity of computational tools to analyze splicing dynamics at single-cell resolution. Here, we present MARVEL, a comprehensive R package for single-cell splicing analysis applicable to RNA sequencing generated from the plate- and droplet-based methods. We performed extensive benchmarking of MARVEL against available tools and demonstrated its utility by analyzing iPSC differentiation into endoderm cells and cardiomyocytes. MARVEL enables systematic and integrated splicing and gene expression analysis of single cells to characterize the splicing landscape and reveal biological insights.
Weight of evidence of Y-STR matches computed with the discrete Laplace method: Impact of adding a suspect’s profile to a reference database
Authors: Andersen Mikkel Meyer , Eriksen Poul Svante , Morling Niels
Published: August 2022

The discrete Laplace method is recommended by multiple parties (including the International Society of Forensic Genetics, ISFG) to estimate the weight of evidence in criminal cases when a suspect’s Y-STR profile matches the crime scene Y-STR profile. Unfortunately, modelling the distribution Y-STR profiles in the database is time-consuming and requires expert knowledge. When the suspect’s Y-STR profile is added to the database, as would be the protocol in many cases, the discrete Laplace model must be recomputed. We found that the likelihood ratios with and without adding the suspect’s Y-STR profile were almost identical with 1,000 or more Y-STR profiles in the database for Y-STR profiles with 8, 12, and 17 loci. Thus, likelihood ratio calculations can be performed in seconds if a an established discrete Laplace model based on at least 1,000 Y-STR profiles is used. A match in a database with 17 Y-STR loci from at least 1,000 male individuals results in a likelihood ratio above 10,000 in approximately 94% of the cases, and above 100,000 in approximately 82% of the cases. We offer a freely available IT tool for estimating the discrete Laplace model of the STR profiles in a database and the likelihood ratio.

Highlights

The discrete Laplace method is suitable for estimating the weight of evidence of matches with 17 Y-STRs.

LRs based on the discrete Laplace method are 10-100 times higher (in median) than those based on Brenner’s κ method.

A database with 17 STRs from at least 1,000 males gives LRs of above 10,000 in approximately 94% of the cases and above 100,000 in approximately 82% of the cases with the discrete Laplace method.

The weight of evidence of a matching Y-STR profile is computed within seconds and easily documented when a precomputed discrete Laplace model is available (an IT tool is provided).

50% of all Yfiler Plus matches are between male relatives within a genetic distance of five meioses.
Widespread horizontal gene transfer between plants and their microbiota
Authors: Haimlich Shelly , Fridman Yulia , Khandal Hitaishi , Savaldi-Goldstein Sigal , Levy Asaf
Published: August 2022

Plants host a large array of commensal bacteria that interact with the host. The growth of both bacteria and plants is often dependent on nutrients derived from the cognate partners, and the bacteria fine-tune host immunity against pathogens. This ancient interaction is common in all studied land plants and is critical for proper plant health and development. We hypothesized that the spatial vicinity and the long-term relationships between plants and their microbiota may promote or even depend on cross-kingdom horizontal gene transfer (HGT), a phenomenon that is relatively rare in nature. To test this hypothesis we analyzed the Arabidopsis thaliana genome and its extensively sequenced microbiome to detect events of horizontal transfer of full length genes that are absent from non-plant associated bacteria. Interestingly, we detected 180 unique genes that were horizontally transferred between plants and their microbiota. Genes transferred from plants to their microbiota are enriched in secreted proteins that metabolize carbohydrates, whereas microbes transferred to plants genes that are enriched in redox homeostasis functions. To validate our approach, we tested if a bacterial gene is functionally similar to its Arabidopsis homologue in planta. The Arabidopsis DET2 gene is essential for biosynthesis of the brassinosteroid phytohormones and loss-of-function of the gene leads to dwarfism. We found that expression of the DET2 homologue from Leifsonia bacteria of the Actinobacteria phylum in the Arabidopsis det2 background complements the mutant, and leads to normal plant growth. Together, these data suggest that cross-kingdom horizontal gene transfer events shape the interactions between plants and their microbiome.

Significance statement

What are the genes that shape host-microbe interactions and what are their origins are fundamental questions in molecular ecology and evolution. We explored the evolutionary mechanisms that formed Arabidopsis-microbiota interactions, as a model for host-microbe interactions. We found prevalent horizontal gene transfer, affecting 180 genes, that occurred between plants and their commensal microbiota. We propose that these genes participate in molecular mimicry between the host and its microbiome. Bacteria acquired from plants genes that primarily encode for secreted proteins that metabolize carbohydrates, thereby enabling bacteria to grow on plant-derived sugars. Additionally, we demonstrate how a bacterial gene that mimics a plant hormone biosynthesis gene can replace the plant gene function. Our results suggest that horizontal gene transfer between hosts and their microbiota is a significant and active evolutionary mechanism that contributed new traits to plants and their commensal microbiota.
Structures of human Malic Enzyme 3
Authors: Grell Tsehai A.J. , Mason Mark , Thompson Aaron A. , Gómez-Tamayo Jose Carlos , Riley Daniel , Wagner Michelle V. , Steele Ruth , Ortiz-Meoz Rodrigo F. , Wadia Jay , Shaffer Paul L. , Tresadern Gary , Sharma Sujata , Yu Xiaodi
Published: August 2022

Malic enzymes (ME1, ME2, and ME3) are involved in cellular energy regulation, redox homeostasis, and biosynthetic processes, through the production of pyruvate and reducing agent NAD(P)H. Recent studies have implicated the third and least well-characterized isoform, mitochondrial NADP+-dependent malic enzyme 3 (ME3), as a therapeutic target for pancreatic cancers. Here, we utilized an integrated structure approach to capture the structures of ME3 in various ligand binding states. ME3 exists as a stable tetramer and its dynamic Domain C is critical for activity. Catalytic assay results reveal that ME3 is a non-allosteric enzyme and does not require modulators for activity while structural analysis suggests that the inner stability of ME3 domain A relative to ME2 disables allostery in ME3. With structural information available for all three malic enzymes, the foundation has been laid to understand the structural and biochemical differences of these enzymes and could aid in the development of specific malic enzyme small molecule drugs.
Discovering genomic islands in unannotated bacterial genomes using sequence embedding
Authors: Banerjee Priyanka , Eulenstein Oliver , Friedberg Iddo
Published: August 2022

Motivation

Genomic islands (GEIs) are clusters of genes in bacterial genomes that are typically acquired by horizontal gene transfer. Genomic islands play a crucial role in the evolution of bacteria by helping them adapt quickly to changing environments. Specifically of interest to human health, many GEIs contain pathogenicity and antimicrobial resistance genes. Detecting GEIs is therefore an important problem in biomedical and environmental research. There have been many previous studies for computationally identifying GEIs, but most of the studies rely either on detecting differences between closely related genomes, or on annotated nucleotide sequences with predictions based on a fixed set of known features.

Results

Here we present TreasureIsland, which uses a new unsupervised representation of DNA sequences to predict GEIs. We developed a high precision boundary detection method featuring an incremental fine-tuning of GEI borders, and we evaluated the accuracy of this framework using a new comprehensive reference dataset, Benbow. We show that TreasureIsland performs competitively when compared with other GEI predictors, enabling the identification of genomic islands in unannotated and taxonomically isolated bacterial genomes.

Availability

The source code and the datasets used in this study are available at: https://github.com/priyamayur/GenomicIslandPrediction

Contact

idoerg@iastate.edu

Supplementary information

Supplementary Material is available at Bioinformatics online.
Does AlphaFold2 model proteins’ intracellular conformations? An experimental test using cross-linking mass spectrometry of endogenous ciliary proteins
Authors: McCafferty Caitlyn L. , Pennington Erin L. , Papoulas Ophelia , Taylor David W. , Marcotte Edward M.
Published: August 2022

A major goal in structural biology is to understand protein assemblies in their biologically relevant states. Here, we investigate whether AlphaFold2 structure predictions match native protein conformations. We chemically cross-linked proteins in situ within intact Tetrahymena thermophila cilia and native ciliary extracts and identified 1,225 intramolecular cross-links within the 100 best-sampled proteins to provide a benchmark of distance restraints obeyed by proteins in their native assemblies. The corresponding AlphaFold2 structure predictions were highly concordant, positioning 86.2% of cross-linked residues within Cα-to-Cα distances of 30 Å, consistent with the known cross-linker length. 43% of the proteins showed no violations. Most inconsistencies occurred in low-confidence regions or between domains of the structure prediction. For basal body protein BBC118, cross-links combined with the predicted structure revealed domain packing satisfying both data. Overall, AlphaFold2 predicted biological structures with low predicted aligned error corresponded to more correct native structures. However, we observe cases where rigid body domains are oriented incorrectly, suggesting that combining structure prediction with experimental information will better reveal biologically relevant conformations.
An uncertainty-based interpretable deep learning framework for breast cancer outcomes prediction
Authors: Chai Hua , Lin Siyin , He Minfan , Yang Yuedong , OuYang Yongzhong , Zhao Huiying
Published: August 2022

Accurate prediction of breast cancer outcomes is important for selecting appropriate treatment, which can prolong the survival period of the patients and improve the life quality. Recently, different deep learning-based methods are carefully designed for cancer outcomes prediction. However, the applications of these methods are still challenging due to the model interpretability. In this study, we proposed a novel multi-task deep neural network UISNet to interpret the feature importance of the prediction model by an uncertainty-based integrated gradients algorithm. Additionally, UISNet improves the prediction accuracy by introducing the prior biological pathway knowledge and utilizing the patients’ heterogeneity information. By applications to seven breast cancer public datasets, the method was shown to outperform state-of-the-art methods by achieving a 5.79% higher C-index value on average. For the identified genes based on the interpretable model, 11 out of the top 20 genes have been proved to be associated with breast cancer by literature review. The comprehensive tests indicated that our proposed method is accurate and robust to predict breast cancer outcomes, and is an effective way to identify the prognosis-related genes. The method codes are available at: https://github.com/chh171/UISNet.
Biodiversity and distribution of sea anemones (Cnidaria, Anthozoa, Actiniaria) in Peru
Authors: Durand Allison , Valdivia-Chávez Deysi , Aramayo Víctor
Published: August 2022

Diverse and abundant sea anemones are common in shallow marine areas. Detailed biodiversity analysis in Peru are comparatively scarce. To contribute to the biodiversity inventory and distribution information of this taxa, we analyzed exhaustively the available bibliography in Peruvian waters. A total of 23 anemone species were identified, distributed in 68 localities, and grouped into 1 Order (Actiniaria), 6 Families (Actiniidae, Actinostolidae, Aiptasiidae, Isanthidae, Phelliidae and Sagartiidae) and 20 Genera. The most reported species areAnthothoe chilensis(37 references),Phymactis clematis(28),Phymanthea pluvia(27),Oulactis concinnata(18), andAntholoba achates(15). Lima is the region with the highest number of publications, followed by La Libertad, Piura, Lambayeque, and Ancash.Anthothoe chilensisoccurs in almost all the Peruvian coastal regions. On the contrary,O. concinnatahas been primarily observed in Lima, whileA. achatesoccurred only in the southern regions (Ica, Arequipa, and Moquegua). Rocky substrates (~55% records) seem to be the most suitable habitat for sea anemones in Peru, corresponding to exposed (e.g. vertical walls) and sheltered zones (e.g. rocky crevices, caves, under rock areas). Although most of the species in Peru exhibit a relatively wide spatial distribution, our results suggest that there are several regions with little or no research efforts. Despite a growing study effort over the past 30 years (>50% of biodiversity reported), the current biodiversity status for this group is still unclear. A significant effort is needed to better analyze occurrence patterns and unveil new species regarding a changing environmental scenario with human influence.