bluuebunny/crossref_metadata_2025 huggingface dataset:
Immunogenomics of cholangiocarcinoma
Authors: Gehl Virag , O’Rourke Colm J. , Andersen Jesper B.
Published: November 2023

The development of cholangiocarcinoma spans years, if not decades, during which the immune system becomes corrupted and permissive to primary tumor development and metastasis. This involves subversion of local immunity at tumor sites, as well as systemic immunity and the wider host response. While immune dysfunction is a hallmark of all cholangiocarcinoma, the specific steps of the cancer-immunity cycle that are perturbed differ between patients. Heterogeneous immune functionality impacts the evolutionary development, pathobiological behavior, and therapeutic response of these tumors. Integrative genomic analyses of thousands of primary tumors have supported a biological rationale for immune-based stratification of patients, encompassing immune cell composition and functionality. However, discerning immune alterations responsible for promoting tumor initiation, maintenance, and progression from those present as bystander events remains challenging. Functionally uncoupling the tumor-promoting or tumor-suppressing roles of immune profiles will be critical for identifying new immunomodulatory treatment strategies and associated biomarkers for patient stratification. This review will discuss the immunogenomics of cholangiocarcinoma, including the impact of genomic alterations on immune functionality, subversion of the cancer-immunity cycle, as well as clinical implications for existing and novel treatment strategies.
LIGHTSITE III: 13-Month Efficacy and Safety Evaluation of Multiwavelength Photobiomodulation in Nonexudative (Dry) Age-Related Macular Degeneration Using the LumiThera Valeda Light Delivery System
Authors: Boyer David , Hu Allen , Warrow David , Xavier Samantha , Gonzalez Victor , Lad Eleonora , Rosen Richard B. , Do Diana , Schneiderman Todd , Hu Allen , Munk Marion R. , Jaffe Glenn , Tedford Stephanie E. , Croissant Cindy L. , Walker Michael , Rückert Rene , Tedford Clark E.
Published: November 2023

Purpose:

The LIGHTSITE III study evaluated multiwavelength photobiomodulation (PBM) therapy in nonexudative (dry) AMD using the LumiThera Valeda® Light Delivery System.

Methods:

LIGHTSITE III is a randomized, controlled trial to assess the safety and effectiveness of PBM in dry AMD. Subjects were treated with multiwavelength PBM (590, 660 and 850 nm) or Sham treatment delivered 9 treatments over 3-5 weeks every four months over 24 months. Subjects were assessed for efficacy and safety outcomes. Data from the 13-month analysis are presented in this report.

Results:

A total of 100 subjects (148 eyes) with dry AMD were randomized. LIGHTSITE III met the primary efficacy BCVA endpoint with a significant difference between PBM (n = 91 eyes) and Sham (n = 54 eyes) groups (Between group difference: 2.4 letters (SE 1.15), CI: -4.7 - -0.1, p = 0.02)(PBM alone: 5.4 letters (SE 0.96), CI: 3.5 - 7.3, p < 0.0001; Sham alone: 3.0 letters (SE 1.13), CI: 0.7 - 5.2, p < 0.0001). The PBM group showed a significant decrease in new onset GA (p = 0.024, Fisher exact test, odds ratio 9.4). A favorable safety profile was observed.

Conclusions:

LIGHTSITE III provides a prospective, randomized controlled trial showing improved clinical and anatomical outcomes in intermediate dry AMD following PBM.
Relative Flow Index as a Novel Optical Coherence Tomography Angiography Biomarker in Primary Open Angle Glaucoma
Authors: Ameen Ismail Ahmed , Hatata Ragai Magdy , Sadek Sherin Hassan
Published: November 2023

Précis:

Relative flow indices as novel optical coherence tomography angiography (OCTA) biomarkers demonstrated reduced optic nerve head and peripapillary large vessel and capillary perfusion in primary open angle glaucoma (POAG). Large vessel perfusion correlated with disease severity and progression.

Purpose:

To introduce relative flow indices as novel OCTA biomarkers and their pathologic insights in POAG.

Materials and Methods:

This is a retrospective case-control study where 57 POAG and 57 control eyes were included. OCTA 4.5×4.5 mm optic nerve head (ONH) were analyzed using ImageJ 1.53t to calculate global flow indices (GFIs) and relative flow indices (RFIs) for whole image optic nerve head, isolated radial peripapillary capillary plexus, and isolated large vessel angiograms.

Results:

Retinal nerve fiber layer thickness (RNFLT), ONH vascular density (VD), except inside disc and large vessel VD, GFIs, and RFIs were lower in POAG than control. There was a positive correlation between RNFLT and both VD and GFIs. Among RFIs, only large vessel RFI (ONHLVRFI) demonstrated a positive correlation with average RNFLT. Linear regression demonstrated a significant positive coefficient for ONHLVRFI with RNFLT as the dependent variable. The area under receiver operating characteristic curve showed diagnostic accuracy ranging fair, good, and excellent for all biomarkers. Inferior RNFLT had the highest area under the curve (0.922) while optic nerve head large vessel density had the lowest (0.523).

Conclusions:

POAG showed structural loss of RNFL neurovascular unit manifesting as positively correlated reduction of VD and RNFLT. Also, POAG had lower global perfusion of the optic nerve head and peripapillary area, resulting in the positively correlated reduction of GFIs and RNFLT. Although RFIs were lower in POAG, only ONHLVRFI demonstrated a positive correlation and regression with RNFLT, implying that large vessel hypoperfusion was associated with POAG severity and progression.
Skin Cancer
Authors: Flowers Lauren , Sandhu Mandeep , Martin Kari
Published: November 2023

Basal cell nevus syndrome is a genetically linked multisystem disorder with a hallmark tendency for development of multiple basal cell carcinomas at a young age. It is associated with a multitude of other anomalies including keratocytes of the jaw, palmar or plantar pits, and ectopic intracranial calcifications. This disease is most commonly caused by loss of function in tumor suppressor gene PTCH1 resulting in overactivation of the Hedgehog pathway and basal cell carcinoma formation. Diagnosis is largely clinical; patients must meet criteria of both major and minor categories. Genetic testing is warranted in specific situations where clinical diagnosis is unclear or for genetic counseling purposes. Given that basal cell carcinoma is a very common dermatologic disorder, it is important to recognize when it arises in the setting of genetically associated diseases. Early detection allows for proper management and surveillance of not only basal cell carcinomas but also the other multisystem effects of basal cell nevus syndrome. This review gives an in-depth overview of the etiology, pathogenesis, diagnosis, and management of basal cell nevus syndrome.
Use of Family Photographs Reduces Restlessness in Neurocritical Care Patients
Authors: Givens Cole , Nairon Emerson B. , Jackson Mona , Vashisht Ayushi , Olson DaiWai M.
Published: November 2023

BACKGROUND:Patients admitted to the neuroscience intensive care unit often experience varying states of confusion and restlessness. The purpose of this study was to examine restlessness in acutely confused patients through use of familiar photographs.METHODS: This randomized prospective pilot study placed family photographs (photos) on the bedrail of confused patients during the night shift (8pmto 4am) in a neuroscience intensive care unit. Wrist actigraphy was used to examine restlessness when patients were turned to face the photos versus when they were not facing the photos.RESULTS:The 20 patients enrolled provided 34 nights worth of data during which 32 640 actigraph readings were obtained. On the first night of study, the odds of wrist movement were higher when the patient was facing the photos compared with not (odds ratio, 1.51; 95% confidence interval, 1.42-1.61). During subsequent nights, the odds of wrist movement were lower when the patient was facing the photos compared with not (odds ratio, 0.82; 95% confidence interval, 0.75-0.90).CONCLUSION: Use of familiar photos does not change restlessness, agitation, or delirium on the first night of observation. However, the use of familiar photos may decrease restlessness on the subsequent nights. There are important subjective observations from researchers and family that suggest all subjects had a noticeable response when initially seeing the familiar photos.
A glimpse into multimodal neuromonitoring in acute liver failure: a case report
Authors: Zorzi Stefano , Ayako Minemura Ordinola Amanda , Cunha De Souza Lima Eduardo , Martins Teixeira Gabriela , Salvagno Michele , Sterchele Elda Diletta , Taccone Fabio Silvio
Published: November 2023

Introduction:

Acute liver failure (ALF) is a rapidly progressing, life-threatening syndrome characterized by liver-related coagulopathy and hepatic encephalopathy (HE). Given that higher HE grades correlate with poorer outcomes, clinical management of ALF necessitates close neurological monitoring. The primary objective of this case report is to highlight the diagnostic value of utilizing multimodal neuromonitoring (MNM) in a patient suffering from ALF.

Case report:

A 56-year-old male patient with a history of chronic alcoholism, without prior chronic liver disease, and recent acetaminophen use was admitted to the hospital due to fatigue and presenting with a mild flapping tremor. The primary hypothesis was an acute hepatic injury caused by acetaminophen intoxication. In the following hours, the patient’s condition deteriorated, accompanied by neurological decline and rising ammonia levels. The patient’s neurological status was closely monitored using MNM. Bilaterally altered pupillary light reflex assessed by decreasing in the Neurological Pupil Index values, using automated pupillometry, initially suggested severe brain oedema. However, ultrasound measurements of the optic nerve sheath diameter showed normal values in both eyes, P2/P1 noninvasive intracranial pressure waveform assessment was within normal ranges and the cerebral computed tomography-scan revealed no signs of cerebral swelling. Increased middle cerebral artery velocities measured by Transcranial Doppler and the initiation of electroencephalography monitoring yielded the presence of status epilepticus.

Discussion:

The utilization of MNM facilitated a more comprehensive understanding of the mechanisms underlying the patient’s clinical deterioration in the setting of HE. Nonetheless, future studies are needed to show feasibility and to yield valuable insights that can enhance the outcomes for patients with HE using such an approach. Given the absence of specific guidelines in this particular context, it is advisable for physicians to give further consideration to the incorporation of MNM in the management of unconscious patients with ALF.
False-Positive Metastatic Disease Due to Bilateral Ectopic Adrenal Tissue
Authors: Li Edward , Anand Kumar Rahul , Chen Jeffrey , Kang Owen , Mansberg Robert
Published: November 2023

A 60-year-old man was referred for staging of prostate cancer. Initial CT scan demonstrated soft tissue lesions in bilateral renal hila, which demonstrated mild68Ga-PSMA avidity and moderate FDG avidity on sequential PET scans suspicious for malignancy. Biopsy confirmed adrenal cortical tissue. This case highlights an exceedingly rare occurrence of ectopic adrenocortical tissue in both renal hila.
Enterovesical Fistula in a Lymphoma Patient Revealed by FDG PET/CT With an Oral Contrast Agents
Authors: Guo Linlin , Shen Guohua
Published: November 2023

A 60-year-old man with colonic diffuse large B-cell lymphoma was referred for FDG PET/CT for initial staging. He was suspected of enterovesical fistula. After oral administration, large amounts of contrast agents accumulated in the bowel lumen and leaked into the bladder through a well-marked fistulous tract. Corresponding to the fistula, a linear pattern of FDG uptake extended from the bladder into the colonic lumen, and the measured SUVmax inside the lesion was as high as that of the urinary bladder. Cystography confirmed the presence of the enterovesical fistula.
Pulmonary Arterial Tumor Embolism From Recurrent Metastatic Renal Cell Carcinoma on FDG PET/CT
Authors: Szabari Margit V. , Ni Chiayi , Davila Diego , Viragh Karoly
Published: November 2023

A 55-year-old man with renal cell carcinoma extending into the renal vein/inferior vena cava (status post nephrectomy and inferior vena cava thrombectomy, pT3bN0M0), and perioperative pulmonary bland thromboembolism (resolved with 3-month of anticoagulation), followed by 3.5 years of complete remission, developed new incidental pulmonary arterial filling defects on a surveillance CT examination (asymptomatic, normal d-dimer, no deep vein thrombosis). Despite anticoagulation, the filling defects not only persisted but also demonstrated intense FDG activity on a restaging PET/CT performed 4 months later for new pulmonary oligometastasis. The FDG activity resolved after systemic immunotherapy, which suggested the retrospective diagnosis of pulmonary arterial tumor emboli, a rare finding.
Polyether Ether Ketone (PEEK) Implants and the Manufacturer and User Facility Device Experience (MAUDE) Database: An Updated Review of Adverse Events and Complications
Authors: Shewmake Connor , Khetpal Sumun , Ozaki Wayne
Published: November 2023

Introduction:

Polyether ether ketone (PEEK) custom implants have been fundamental in addressing bone malformations and restoring traumatic defects within the field of craniofacial surgery. Although such implants are generally considered safe and appropriate alternatives to autologous bone grafts, there has been a lack of standardized reporting of adverse events associated with PEEK implants. The purpose of this study is multi-fold: (1) to explore the current landscape of autologous and allogeneic materials utilized for bone grafting; (2) to analyze and characterize adverse events associated within PEEK implants from the widely accredited, FDA-run database, Manufacturer and User Facility Device Experience (MAUDE); and using the data, (3) to provide guidance to craniofacial surgeons using PEEK implants in their surgical practice.

Material/Methods:

A retrospective review of the adverse events associated with PEEK implants were performed through the FDA-run database, Manufacturer and User Facility Device Experience (MAUDE). The database was surveyed from July 2013 to January 2023. Event types were categorized by injury or malfunction, and device-reported adverse events were recorded, respectively.

Results:

Database search initially yielded 77 adverse event reports, but after duplicates were removed, 69 event reports were included in the analysis. These events were sorted into the following categories: device-related and patient-related. Event types were categorized by injury (48.3%) or malfunction (53.6%). The most common reported device-related adverse events were “Poor Fit” (53.6%) and “Adverse Event without Identified Use or Problem “ (26.1%). The most common reported patient-related event was “Infection” (32.8%). Of these adverse event reports, 14 (20.2%) patients required a second surgery; 21(30.4%) required implant modification whereas in the operating room; 17 (24.6%) underwent implant removal. Nine (13%) patients experienced operative case delays due to implant modifications.

Conclusion:

Infection and poor fit were among the most commonly reported adverse events associated with PEEK customizable implants. Although PEEK implants have been widely implemented in addressing craniofacial bony defects, our database analysis does call for further investigation in studying the long-term outcomes associated with PEEK craniofacial implants. With such analyses and collaboration among plastic surgeons and device engineers, there is great opportunity for innovation of these devices.
Surgical Guide Splint Fabrication via Virtual Surgical Planning for Complex Mandible Fractures in the Trauma Setting
Authors: Koenig Zachary A. , Lokant Bradley T. , Weaver Samantha , Brooke Sebastian M. , Uygur Halil S.
Published: November 2023

Introduction:

In cases of significantly displaced or comminuted mandible fractures, surgical guide splints can be developed to create the normal preinjury occlusion rather than placing patients in maxillomandibular fixation. Standard fracture fixation involves bending of plates intraoperatively based on surgeon-constructed dental splints which is prone to error.

Methods:

A 38-year-old male experienced a gunshot wound to the face that resulted in mandibular angle fractures bilaterally causing severely deranged occlusion and free-floating anterior mandible segment. Virtual surgical planning (VSP) software was used to recreate the injury-induced anatomy and anticipated postoperative anatomy. It also provided a surgical guide splint and a framework to preoperatively bend reconstruction plates to assist in achieving proper occlusion.

Results:

He underwent open reduction internal fixation of comminuted mandible fractures with lingual guide splint placement 10 days after injury. Following lingual splint application, the reconstruction plate was applied from angle to angle. The lingual splint was maintained for 3 weeks postoperatively to support the stabilization, and he was able to tolerate a regular diet and showed no evidence of wound breakdown.

Discussion:

Virtual surgical planning has had important implications in craniofacial surgery, orthognathic surgery, maxillomandibular reconstruction, and orbital reconstruction after tumor resection, temporomandibular joint surgery, and others. However, there have only been isolated reports describing the role of VSP in the facial trauma setting. In this technical study, the authors demonstrate the benefits of VSP and surgical guide splinting in trauma settings.
Wilbrand Knee Revisited
Authors: Shin Robert K. , Kachhela Jaydeep , Tang Cha-Min
Published: November 2023

Background:

Over a century ago, German ophthalmologist Hermann Wilbrand reported inferonasal crossing fibers within the chiasm curve anteriorly into the contralateral optic nerve. This anatomic bend, “Wilbrand knee,” is classically cited as the explanation for the “junctional scotoma,” a contralateral superotemporal visual field defect associated with lesions affecting the optic nerve at its junction with the chiasm. More recent reports have called into question the existence of Wilbrand knee or suggested that it may simply be an artifact.

Methods:

Four human optic chiasms (obtained from cadaver donors with no reported premortem visual pathology) and 2 monkey chiasms were fixed and thin sectioned (40 µm), then examined using anisotropic scattering imaging, a novel technique that takes advantage of the fact that light reflects off well-defined linear structures (i.e., axonal tracts) in a predictable manner based on their orientation. Using this technique, tissue structures oriented in different directions can be distinguished at high resolution without the need for tissue staining.

Results:

In all 4 human optic chiasms, thin fiber tracts consistent with, but less prominent than, those Wilbrand had described were observed. No such tracts were found in the monkey chiasms.

Conclusions:

Wilbrand knee exists in humans but is modest in its anterior projection. Wilbrand knee does not seem to be present in monkeys, however, which may explain conflicting reports in the literature regarding its existence.
Barriers to upper gastrointestinal screening among the general population in high-prevalence areas: a cross-sectional study
Authors: Chen Xin , Ze Yuan , Yi Wanya , Yang Yuling , Sun Renjuan , Tu Huiming
Published: November 2023

Background:

In China, there are large differences between regions in the use of gastroscopies and public awareness of upper gastrointestinal (UGI) screening.

Objective:

This study investigated the current context and analyzed the barriers that influence UGI screening behavior among the general population in UGI cancer high-prevalence areas.

Methods:

A total of 320 participants anonymously answered an online questionnaire. The rank sum test was used to analyze the difference in the scores of the UGI screening awareness questionnaire among participants with different socio-demographic characteristics. Using the awareness level of UGI screening and gastroscopy as the dependent variable, and the socio-demographic characteristics as the independent variable, simple linear regression and binary logistic regression analysis were used to determine the factors influencing attitudes toward gastroscopy screening. We used Spearman's correlation analysis to examine the correlation between UGI screening awareness level and willingness to undergo a gastroscopy.

Results:

There was a correlation between the willingness to undergo gastroscopy and the awareness level of UGI screening (r = 0.243, p < 0.001). Linear regression analysis found that age, type of residence, education level, employment status, monthly income, history of gastroscopy, dietary habits, physical exercise, and convenience in obtaining information were significantly correlated with the awareness level of UGI screening (p < 0.05). Binary logistic regression analysis found that factors significantly associated with gastric cancer screening behavior include residence, monthly income, and self-perceived health status (p < 0.05).

Conclusion:

It is necessary to improve education about UGI cancer and screening knowledge, with a focus on populations with lower education and income.
Adverse childhood experiences predict internet gaming disorder in university students: the mediating role of resilience
Authors: Ma Jinghao , Yang Bo , Wang Shizhen , Yao Yujie , Wu Chencheng , Li Mei , Dong Guang-Heng
Published: November 2023

Background

To investigate the relationship between adverse childhood experiences and internet gaming disorder (IGD) and the mediating role of resilience in the relationship between these two factors.

Methods

The adverse childhood experience scale, resilience scale and IGD Scale were administered to 9349 university students. Correlations and mediating effects were calculated among these scores.

Results

After controlling for sex and age, significant correlations among adverse childhood experiences, resilience and IGD were observed; resilience was a partial mediator variable in the relationship between adverse childhood experiences and IGD.

Conclusions

The more adverse childhood experiences an individual has, the less their mental toughness and the greater their tendency to become addicted to internet games. Adverse childhood experiences can effectively predict IGD, and the risk of becoming addicted to the internet can be decreased by increasing one's mental toughness.
A case of pleural Mycobacterium tuberculosis infection with reversion of Quantiferon Gold Plus results.
Authors: Goire Namraj , Suchard Melinda , Barling Andrew , Fernando Ruchira , Dreyer Linda , Mahony Andrew
Published: November 2023

Introduction: Mycobacterium tuberculosis (MTB) infections continue to have a high mortality and morbidity burden globally. Interferon-Gamma Release Assays (IGRA) such as Quantiferon Gold Plus (QFT-Plus) aid significantly in diagnosis of latent TB. We present a case of active extra-pulmonary MTB infection with reversion of IGRA result as well as negative Xpert MTB/RIF Ultra PCR result from tissues obtained from pleural biopsy.
Case summary: A 52-year-old male presented in August 2022 with a two-week history of pleuritic chest pain associated with modest elevation in inflammatory markers. The patient had had a positive QFG-Plus result in 2018, however QFG-Plus during this admission was negative. Needle thoracocentesis showed an exudative left pleural effusion with predominant lymphocytes. The patient’s symptoms failed to resolve with empiric antimicrobial therapy for community-acquired pneumonia.  Broncho-Alveolar Lavage as well as biopsies of pleural tissues via video-assisted thoracoscopic surgery from the left lower lobe yielded negative results on routine microbiological culture as well as Xpert Ultra PCR. Growth of acid fast bacilli was noted from mycobacterial cultures of pleural tissues which were identified as MTB.
Conclusion: Despite significant technological advances, microbiological diagnosis of MTB infections remains challenging. We document QFG reversion during development from latent to active pleural TB. Decline in the ability of CD4 and CD8 T cells to produce interferon gamma in response to TB antigens was likely associated with loss of host control of latent MTB. This case serves as a reminder that despite exhaustive testing with state-of-art diagnostic platforms, MTB infections can still elude discovery.
A Photoactivatable Norepinephrine for Probing Adrenergic Neural Circuits
Authors: Cahill Michelle K. , Perez Yeraldith Rojas , Larpthaveesarp Amara , Etchenique Roberto , Poskanzer Kira E.
Published: November 2023

Norepinephrine (NE) is a critical neuromodulator that mediates a wide range of behavior and neurophysiology, including attention, arousal, plasticity, and memory consolidation. A major source of NE is the brainstem nucleus the locus coeruleus (LC), which sends widespread projections throughout the central nervous system (CNS). Efforts to dissect this complex noradrenergic circuitry have driven the development of many tools that detect endogenous NE or modulate widespread NE release via LC activation and inhibition. While these tools have enabled research that elucidates physiological roles of NE, additional tools to probe these circuits with a higher degree of spatial precision could enable a finer delineation of function. Here, we describe the synthesis and chemical properties of a photo-activatable NE, [Ru(bpy)2(PMe3)(NE)]PF6(RuBi-NE). We validate the one-photon (1P) release of NE using whole-cell patch clamp electrophysiology in acute mouse brain slices containing the LC. We show that a 10 ms pulse of blue light, in the presence of RuBi-NE, briefly modulates the firing rate of LC neurons via α-2 adrenergic receptors. The development of a photo-activatable NE that can be released with light in the visible spectrum provides a new tool for fine-grained mapping of complex noradrenergic circuits, as well as the ability to probe how NE acts on non-neuronal cells in the CNS.
Using cluster-based permutation tests to estimate MEG/EEG onsets: how bad is it?
Authors: Rousselet Guillaume A.
Published: November 2023

Localising effects in space, time and other dimensions is a fundamental goal of magneto- and electro-encephalography (EEG) research. A popular exploratory approach applies mass-univariate statistics followed by cluster-sum inferences, an effective way to correct for multiple comparisons while preserving high statistical power by pooling together neighbouring effects. Yet, these cluster-based methods have an important limitation: each cluster is associated with a uniquepvalue, such that there is no error control at individual time points, and one must be cautious about interpreting when and where effects start and end. Sassenhagen & Draschkow (2019) provided an important reminder of this limitation. They also reported results from a simulation, suggesting that onsets estimated from EEG data are both positively biased and very variable. However, the simulation lacked comparisons to other methods. Here I report such comparisons in a new simulation, replicating the positive bias of the cluster-sum method, but also demonstrating that it performs relatively well, in terms of bias and variability, compared to other methods that provide point-wisepvalues: two methods that control the false discovery rate, and two methods that control the family-wise error rate (cluster-depth and maximum statistic methods). I also present several strategies to reduce estimation bias, including group calibration, group comparison, and using binary segmentation, a simple change point detection algorithm that outperformed mass-univariate methods in simulations. Finally, I demonstrate how to generate onset hierarchical bootstrap confidence intervals that integrate variability over trials and participants, a substantial improvement over standard group approaches that ignore measurement uncertainty.
Snowball: a novel gene family required for developmental patterning in fruiting bodies of mushroom-forming fungi (Agaricomycetes)
Authors: Földi Csenge , Merényi Zsolt , Balázs Bálint , Csernetics Árpád , Miklovics Nikolett , Wu Hongli , Hegedüs Botond , Virágh Máté , Hou Zhihao , Liu Xiao-Bin , Galgóczy László , Nagy László G.
Published: November 2023

The morphogenesis of sexual fruiting bodies of fungi is a complex process determined by a genetically encoded program. Fruiting bodies reached the highest complexity levels in the Agaricomycetes, yet, the underlying genetics is currently poorly known. In this work, we functionally characterized a highly conserved unannotated gene termedsnb1, whose expression level increases rapidly during fruiting body initiation. According to phylogenetic analyses, orthologues ofsnb1are present in almost all agaricomycetes and may represent a novel conserved gene family that plays a substantial role in fruiting body development. We disruptedsnb1using CRISPR/Cas9 in the agaricomycete model organismCoprinopsis cinerea. Snb1deletion mutants formed unique, snowball-shaped, rudimentary fruiting bodies that could not differentiate caps, stipes and lamellae. We took advantage of this phenotype to study fruiting body differentiation using RNA-Seq analyses. This revealed differentially regulated genes and gene families that, based on wild-type RNA-Seq data, were upregulated early during development and showed tissue-specific expression, underscoring their potential role in differentiation. Taken together, the novel gene family ofsnb1and the differentially expressed genes in thesnb1mutants provide valuable insights into the complex mechanisms underlying developmental patterning in the Agaricomycetes.

Importance

Fruiting bodies of mushroom-forming fungi (Agaricomycetes) are complex multicellular structures, with a spatially and temporally integrated developmental program that is, however, currently poorly known. In this study we present a novel, conserved gene family, Snowball (snb), termed after the unique, differentiation-less fruiting body morphology ofsnb1knockout strains in the model mushroomCoprinopsis cinerea. Snbis a hitherto unannotated gene that is highly conserved among agaricomycetes and encodes a protein of unknown function. A comparative transcriptomic analysis of the early developmental stages of differentiated wild-type and non-differentiated mutant fruiting bodies revealed conserved differentially expressed genes which may be related to tissue differentiation and developmental patterning fruiting body development.
Multifaceted impact of specialized neuropeptide-intensive neurons on the selective vulnerability in Alzheimer’s disease
Authors: Li Manci , Flack Nichole , Larsen Peter A.
Published: November 2023

INTRODUCTION

Widespread disruption of neuropeptide (NP) networks in Alzheimer’s disease (AD) and disproportionate absence of neurons expressinghighNP-producing, coined as HNP neurons, have been reported for the entorhinal cortex (EC) of AD brains. Hypothesizing that functional features of HNP neurons are involved in the early pathogenesis of AD, we aim to understand the molecular mechanisms underlying these observations.

METHODS

Multiscale and spatiotemporal transcriptomic analysis was used to investigate AD-afflicted and healthy brains. Our focus encompassed NP expression dynamics in AD,AD-associatedNPs (ADNPs) trajectories with aging, and the neuroanatomical distribution of HNP neuron.

RESULTS

Findings include that 1) HNP neurons exhibited heightened metabolic needs and an upregulation of gene expressions linked to protein misfolding; 2) dysfunctions of ADNP production occurred in aging and mild cognitive decline; 3) HNP neurons co-expressing ADNPs were preferentially distributed in brain regions susceptible to AD.

DISCUSSION

We identified potential mechanisms that contribute to the selective vulnerability of HNP neurons to AD. Our results indicate that the functions of HNP neurons predispose them to oxidative stress and protein misfolding, potentially serving as inception sites for misfolded proteins in AD.
kmerDB: A Database Encompassing the Set of Genomic and Proteomic Sequence Information for Each Species
Authors: Mouratidis Ioannis , Baltoumas Fotis A. , Chantzi Nikol , Chan Candace S.Y. , Montgomery Austin , Konnaris Maxwell A. , Georgakopoulos George C. , Das Anshu , Chartoumpekis Dionysios , Kovac Jasna , Pavlopoulos Georgios A. , Georgakopoulos-Soares Ilias
Published: November 2023

The rapid decline in sequencing cost has enabled the generation of reference genomes and proteomes for a growing number of organisms. However, at the present time, there is no established repository that provides information about organism-specific genomic and proteomic sequences of certain lengths, also known as kmers, that are either present or absent in each genome or proteome. In this article, we present kmerDB, a database accessible through an interactive web interface that provides kmer based information from genomic and proteomic sequences in a systematic way. kmerDB currently contains 202,340,859,107 base pairs and 19,304,903,356 amino acids, spanning 45,785 and 22,386 reference genomes and proteomes, respectively, as well as 14,658,776 and 149,264,442 genomic and proteomic species-specific sequences, termed quasi-primes. Additionally, we provide access to 5,186,757 nucleic and 214,904,089 peptide sequences that are absent from every genome and proteome, termed primes. kmerDB features a user-friendly interface offering various search options and filters for easy parsing and searching. The service is available at:www.kmerdb.com.
Branch Length Transforms using Optimal Tree Metric Matching
Authors: Arasti Shayesteh , Tabaghi Puoya , Tabatabaee Yasamin , Mirarab Siavash
Published: November 2023

The abundant discordance between evolutionary relationships across the genome has rekindled interest in ways of comparing and averaging trees on a shared leaf set. However, most attempts at reconciling trees have focused on tree topology, producing metrics for comparing topologies and methods for computing median tree topologies. Using branch lengths, however, has been more elusive, due to several challenges. Species tree branch lengths can be measured in many units, often different from gene trees. Moreover, rates of evolution change across the genome, the species tree, and specific branches of gene trees. These factors compound the stochasticity of coalescence times. Thus, branch lengths are highly heterogeneous across both the genome and the tree. For many downstream applications in phylogenomic analyses, branch lengths are as important as the topology, and yet, existing tools to compare and combine weighted trees are limited. In this paper, we make progress on the question of mapping one tree to another, incorporating both topology and branch length. We define a series of computational problems to formalize finding the best transformation of one tree to another while maintaining its topology and other constraints. We show that all these problems can be solved in quadratic time and memory using a linear algebraic formulation coupled with dynamic programming preprocessing. Our formulations lead to convex optimization problems, with efficient and theoretically optimal solutions. While many applications can be imagined for this framework, we apply it to measure species tree branch lengths in the unit of the expected number of substitutions per site while allowing divergence from ultrametricity across the tree. In these applications, our method matches or surpasses other methods designed directly for solving those problems. Thus, our approach provides a versatile toolkit that finds applications in similar evolutionary questions.

Code availability

The software is available athttps://github.com/shayesteh99/TCMM.git.

Data availability

Data are available on Githubhttps://github.com/shayesteh99/TCMM-Data.git.
Effects of testosterone and metformin on the GlycanAge index of biological age and the composition of the IgG glycome
Authors: Vinicki Martina , Pribić Tea , Vučković Frano , Frkatović-Hodžić Azra , Plaza-Andrade Isaac , Tinahones Francisco , Raffaele Joseph , Fernández-García José Carlos , Lauc Gordan
Published: November 2023

With aging, there is a correlation between a decline in the body’s ability to maintain regular functioning and greater susceptibility to age-related diseases. Therapeutic interventions targeting the underlying biological changes of aging hold promise for preventing or delaying multiple age-related diseases. Metformin, a drug commonly used for diabetes treatment, has emerged as a potential gerotherapeutic agent due to its established safety record and preclinical and clinical data on its anti-aging effects. Glycosylation, one of the most common and complex co- and post-translational protein modifications, plays a crucial role in regulating protein function and has been linked to aging and various diseases. Changes in IgG glycosylation patterns have been observed with age, and these alterations may serve as valuable biomarkers for disease predisposition, diagnosis, treatment monitoring, and overall health assessment. In this study, we analyzed the IgG glycosylation patterns of individuals under treatment with metformin, testosterone, metformin plus testosterone and placebo, and investigated the longitudinal changes in glycosylation over time. We observed statistically significant differences in the IgG glycome composition between participants on testosterone therapy and placebo, with decreased agalactosylation and increased galactosylation and sialylation. However, metformin therapy did not result in statistically significant changes in glycosylation patterns. These findings contribute to our understanding of the impact of therapeutic interventions on IgG glycosylation and confirm the value of IgG glycosylation as a significant biomarker, capable of assessing biological age using the GlycanAge index and providing insight into overall health compared to chronological age.
DIISCO: A Bayesian framework for inferring dynamic intercellular interactions from time-series single-cell data
Authors: Park Cameron , Mani Shouvik , Beltran-Velez Nicolas , Maurer Katie , Gohil Satyen , Li Shuqiang , Huang Teddy , Knowles David A. , Wu Catherine J. , Azizi Elham
Published: November 2023

Characterizing cell-cell communication and tracking its variability over time is essential for understanding the coordination of biological processes mediating normal development, progression of disease, or responses to perturbations such as therapies. Existing tools lack the ability to capture time-dependent intercellular interactions, such as those influenced by therapy, and primarily rely on existing databases compiled from limited contexts. We present DIISCO, a Bayesian framework for characterizing the temporal dynamics of cellular interactions using single-cell RNA-sequencing data from multiple time points. Our method uses structured Gaussian process regression to unveil time-resolved interactions among diverse cell types according to their co-evolution and incorporates prior knowledge of receptor-ligand complexes. We show the interpretability of DIISCO in simulated data and new data collected from CAR-T cells co-cultured with lymphoma cells, demonstrating its potential to uncover dynamic cell-cell crosstalk.

Availability

DIISCO is publicly accessible athttps://github.com/azizilab/DIISCO_public. All data will be deposited to GEO upon publication.
Integrative multiomics analysis of neointima proliferation in human saphenous vein: implications for bypass graft disease
Authors: Kim David , Goo Brandee , Shi Hong , Coffey Philip , Veerapaneni Praneet , Chouhaita Ronnie , Cyriac Nicole , Aboud Ghaith , Cave Stephen , Greenway Jacob , Mundkur Rohan , Ahmadieh Samah , Harb Ragheb , Ogbi Mourad , Fulton David J. , Huo Yuqing , Zhang Wei , Long Xiaochun , Guha Avirup , Kim Ha Won , Shi Yang , Rice Robert D. , Gallo Dominic R. , Patel Vijay , Lee Richard , Weintraub Neal L.
Published: November 2023

Introduction

Human saphenous veins (SV) are widely used as grafts in coronary artery bypass (CABG) surgery but often fail due to neointima proliferation (NP). NP involves complex interplay between vascular smooth muscle cells (VSMC) and fibroblasts. Little is known, however, regarding the transcriptomic and proteomic dynamics of NP. Here, we performed multi-omics analysis in anex vivotissue culture model of NP in human SV procured for CABG surgery.

Methods and results

Histological examination demonstrated significant elastin degradation and NP (indicated by increased neointima area and neointima/media ratio) in SV subjected to tissue culture. Analysis of data from 73 patients suggest that the process of SV adaptation and NP may differ according to sex and body mass index. RNA sequencing confirmed upregulation of pro-inflammatory and proliferation-related genes during NP and identified novel processes, including increased cellular stress and DNA damage responses, which may reflect tissue trauma associated with SV harvesting. Proteomic analysis identified upregulated extracellular matrix-related and coagulation/thrombosis proteins and downregulated metabolic proteins. Spatial transcriptomics detected transdifferentiating VSMC in the intima on the day of harvesting and highlighted dynamic alterations in fibroblast and VSMC phenotype and behavior during NP. Specifically, we identified new cell subpopulations contributing to NP, includingSPP1+, LGALS3+VSMC andMMP2+, MMP14+fibroblasts.

Conclusion

Dynamic alterations of gene and protein expression occur during NP in human SV. Identification of the human-specific molecular and cellular mechanisms may provide novel insight into SV bypass graft disease.
Deciphering the Functional Roles of Individual Cancer Alleles Across Comprehensive Cancer Genomic Studies
Authors: Ma Jiayan (Yoshii) , Ting Stephanie , Tam Bartholomew , Pham Timothy , Reich Michael , Mesirov Jill , Tamayo Pablo , Kim William
Published: November 2023

Cancer genome data has been growing in both size and complexity, primarily driven by advances in next-generation sequencing technologies, such as Pan-cancer data from TCGA, ICGC, and single-cell sequencing. Yet, discerning the functional role of individual genomic lesions remains a substantial challenge due to the complexity and scale of the data. Previously, we introduced REVEALER, which identifies groups of genomic alterations that significantly associate with target functional profiles or phenotypes, such as pathway activation, gene dependency, or drug response. In this paper, we present a new mathematical formulation of the algorithm. This version (REVEALER 2.0) is considerably more powerful than the original, allowing for rapid processing and analysis of much larger datasets and facilitating higher-resolution discoveries at the level of individual alleles. REVEALER 2.0 employs the Conditional Information Coefficient (CIC) to pinpoint features that are either complementary or mutually exclusive but still correlate with the target functional profile. The aggregation of these features provides a better explanation for the target functional profile than any single alteration on its own. This is indicative of scenarios where several activating genomic lesions can initiate or stimulate a key pathway or process. We replaced the initial three-dimensional kernel estimation with multiple precomputed one-dimensional kernel estimations, resulting in an approximate 150x increase in speed and efficiency. This improvement, combined with its efficient execution, makes REVEALER 2.0 suitable for much larger datasets and a more extensive range of genomic challenges.
DeepLabCut-based Behavioural and Posture Analysis in a Cricket
Authors: Hayakawa Shota , Kataoka Kosuke , Yamamoto Masanobu , Asahi Toru , Suzuki Takeshi
Published: November 2023

Circadian rhythms are indispensable intrinsic programs that regulate the daily rhythmicity of physiological processes, such as feeding and sleep. The cricket has been employed as a model organism for understanding the neural mechanisms underlying circadian rhythms in insects. However, previous studies measuring rhythm-controlled behaviours only analysed locomotive activity using seesaw-type and infrared sensor-based actometers. Meanwhile, advances in deep learning techniques have made it possible to analyse animal behaviour and posture using software that is devoid of human bias and does not require physical tagging of individual animals. Here, we present a system that can simultaneously quantify multiple behaviours in individual crickets, such as locomotor activity, feeding, and sleep-like states, in the long-term, using DeepLabCut, a supervised machine learning-based software for body keypoints labeling. Our system successfully labelled the six body parts of a single cricket with a high level of confidence and produced reliable data showing the diurnal rhythms of multiple behaviours. Our system also enabled the estimation of sleep-like states by focusing on posture, instead of immobility time, which is a conventional parameter. We anticipate that this system will provide an opportunity for simultaneous and automatic prediction of cricket behaviour and posture, facilitating the study of circadian rhythms.
Flock response to sustained asynchronous predator attacks
Authors: Mohapatra Siddhant , Mahapatra Pallab Sinha
Published: November 2023

Collective behaviour is a ubiquitous emergent phenomenon where organisms share information and conduct complicated manoeuvres as a group. Dilution of predation risk is presumed to be a major proponent contributing towards the emergence of such fascinating behaviour. However, the role of multiple sources of predation risk in determining the characteristics of the escape manoeuvres remains largely unexplored. The current work aims to address this paucity by examining the response of a flock to multiple persistently pursuing predators, using an agent-based approach employing a force-based model. Collective features such as herding, avoiding and split-and-join are observed across a wide spectrum of systemic conditions. The transition from one response state to another is examined as a function of the relative angle of predator attack, a parameter exclusive to multi-predator systems. Other concomitant parameters, such as the frequency of attacks and compatibility of target selection tactics of the predators, have a significant effect on the escape probability of the prey (i.e., the success rate of escape manoeuvres). A quantitative analysis has been carried out to determine the most successful combination of target selection while also focusing on beneficial ancillary effects such as flock splitting. The long-term dynamics of the system indicate a faster decay of prey numbers (higher prey mortality) at higher coordination strength due to a monotonically decreasing relation between coordination strength and prey speed supplanted by coincidental synchrony of predator attacks. The work highlights the non-additive nature of the effects of predation in a multi-predator system and urges further scrutiny of group hunting dynamics in such systems.

Author summary

Collective motion is a natural phenomenon observed across a wide range of length and time scales. One purported reason for the development of such behaviour is to reduce the individual risk of predation through the many-eyes effect and group manoeuvring in case of attacks. However, the behaviour of the prey flock can turn out to be starkly different when there are multiple predators involved. We examine the response of the flock in the presence of multiple predators and find the circumstances leading to the occurrence of different escape manoeuvres. We observe the stricter penalty warranted on the flock due to certain manoeuvres, such as split-and-join, due to the asynchronous and persistent nature of the predator attacks. We also identify the issues with superfluous coordination among prey and its ramifications in terms of prey mortality. The combined effect of the predators is found to outpace the sum of individual predator prowess. The current work emphasises the distinct dynamics of a multi-predator system and puts forth pertinent queries regarding synchronisation among predators and group hunting tactics.