bluuebunny/crossref_metadata_2025 huggingface dataset:
Machine learning classification of diagnostic accuracy in pathologists interpreting breast biopsies
Authors: Brunyé Tad T , Booth Kelsey , Hendel Dalit , Kerr Kathleen F , Shucard Hannah , Weaver Donald L , Elmore Joann G
Published: November 2023

Objective

This study explores the feasibility of using machine learning to predict accurate versus inaccurate diagnoses made by pathologists based on their spatiotemporal viewing behavior when evaluating digital breast biopsy images.

Materials and Methods

The study gathered data from 140 pathologists of varying experience levels who each reviewed a set of 14 digital whole slide images of breast biopsy tissue. Pathologists’ viewing behavior, including zooming and panning actions, was recorded during image evaluation. A total of 30 features were extracted from the viewing behavior data, and 4 machine learning algorithms were used to build classifiers for predicting diagnostic accuracy.

Results

The Random Forest classifier demonstrated the best overall performance, achieving a test accuracy of 0.81 and area under the receiver-operator characteristic curve of 0.86. Features related to attention distribution and focus on critical regions of interest were found to be important predictors of diagnostic accuracy. Further including case-level and pathologist-level information incrementally improved classifier performance.

Discussion

Results suggest that pathologists’ viewing behavior during digital image evaluation can be leveraged to predict diagnostic accuracy, affording automated feedback and decision support systems based on viewing behavior to aid in training and, ultimately, clinical practice. They also carry implications for basic research examining the interplay between perception, thought, and action in diagnostic decision-making.

Conclusion

The classifiers developed herein have potential applications in training and clinical settings to provide timely feedback and support to pathologists during diagnostic decision-making. Further research could explore the generalizability of these findings to other medical domains and varied levels of expertise.
Platinum ineligibility and survival outcomes in patients with advanced urothelial carcinoma receiving first-line treatment
Authors: Gupta Shilpa , Andreev-Drakhlin Alexander , Fajardo Otto , Fassò Marcella , Garcia Jorge A , Wee Christopher , Schröder Carsten
Published: November 2023

Background

This study examined real-world patients with locally advanced or metastatic urothelial carcinoma considered ineligible for platinum-containing chemotherapy in the first-line setting.

Methods

This retrospective observational study used data from a nationwide (United States) de-identified patient-level electronic health record–derived database. Eligible adults (aged 18 years and older) had a locally advanced or metastatic urothelial carcinoma diagnosis on or after January 1, 2016, and initiated first-line systemic treatment at least 90 days before December 31, 2021. Platinum ineligibility was defined as Eastern Cooperative Oncology Group performance status of at least 3, creatinine clearance less than 30 mL/min, or Eastern Cooperative Oncology Group performance status of 2 and creatinine clearance of less than 45 mL/min. Overall survival and real-world progression-free survival (PFS) were summarized using the Kaplan–Meier method.

Results

The overall population comprised 4270 patients; 477 (11%) were considered platinum ineligible, 262 (55%) received a first-line programmed cell death 1 or programmed cell death ligand 1 immune checkpoint inhibitor, and 118 (25%) received platinum-based chemotherapy. A total of 2335 (55%) patients were platinum eligible; 677 (29%) received a first-line programmed cell death 1 or programmed cell death ligand 1 inhibitor, and 1229 (53%) received platinum-based chemotherapy. Median overall survival was 13.3 months (95% confidence interval [CI] = 12.4 to 14.8 months) in platinum-eligible and 5.1 months (95% CI = 4.2 to 6.4 months) in platinum-ineligible patients. Median PFS was shorter in platinum-ineligible (3.4 months; 95% CI = 2.9 to 4.0 months) vs platinum-eligible patients (5.9 months; 95% CI = 5.5 to 6.2 months) overall and when stratified by first-line therapy type.

Conclusion

This real-world study has shown for the first time the treatment patterns and outcomes in newly diagnosed patients with locally advanced or metastatic urothelial carcinoma ineligible for platinum-based chemotherapy. These findings provide quantitative benchmarks for platinum ineligibility in the first-line advanced or metastatic urothelial carcinoma setting and highlight the need for novel therapy options.
Molluscan Genomes Reveal Extensive Differences in Photopigment Evolution Across the Phylum
Authors: McElroy Kyle E , Audino Jorge A , Serb Jeanne M
Published: November 2023

In animals, opsins and cryptochromes are major protein families that transduce light signals when bound to light-absorbing chromophores. Opsins are involved in various light-dependent processes, like vision, and have been co-opted for light-independent sensory modalities. Cryptochromes are important photoreceptors in animals, generally regulating circadian rhythm, they belong to a larger protein family with photolyases, which repair UV-induced DNA damage. Mollusks are great animals to explore questions about light sensing as eyes have evolved multiple times across, and within, taxonomic classes. We used molluscan genome assemblies from 80 species to predict protein sequences and examine gene family evolution using phylogenetic approaches. We found extensive opsin family expansion and contraction, particularly in bivalve xenopsins and gastropod Go-opsins, while other opsins, like retinochrome, rarely duplicate. Bivalve and gastropod lineages exhibit fluctuations in opsin repertoire, with cephalopods having the fewest number of opsins and loss of at least 2 major opsin types. Interestingly, opsin expansions are not limited to eyed species, and the highest opsin content was seen in eyeless bivalves. The dynamic nature of opsin evolution is quite contrary to the general lack of diversification in mollusk cryptochromes, though some taxa, including cephalopods and terrestrial gastropods, have reduced repertoires of both protein families. We also found complete loss of opsins and cryptochromes in multiple, but not all, deep-sea species. These results help set the stage for connecting genomic changes, including opsin family expansion and contraction, with differences in environmental, and biological features across Mollusca.
Self-delivering, chemically modified CRISPR RNAs for AAV co-delivery and genome editing in vivo
Authors: Zhang Han , Kelly Karen , Lee Jonathan , Echeverria Dimas , Cooper David , Panwala Rebecca , Amrani Nadia , Chen Zexiang , Gaston Nicholas , Wagh Atish , Newby Gregory A , Xie Jun , Liu David R , Gao Guangping , Wolfe Scot A , Khvorova Anastasia , Watts Jonathan K , Sontheimer Erik J
Published: November 2023

Guide RNAs offer programmability for CRISPR-Cas9 genome editing but also add challenges for delivery. Chemical modification, which has been key to the success of oligonucleotide therapeutics, can enhance the stability, distribution, cellular uptake, and safety of nucleic acids. Previously, we engineered heavily and fully modified SpyCas9 crRNA and tracrRNA, which showed enhanced stability and retained activity when delivered to cultured cells in the form of the ribonucleoprotein complex. In this study, we report that a short, fully stabilized oligonucleotide (a ‘protecting oligo’), which can be displaced by tracrRNA annealing, can significantly enhance the potency and stability of a heavily modified crRNA. Furthermore, protecting oligos allow various bioconjugates to be appended, thereby improving cellular uptake and biodistribution of crRNA in vivo. Finally, we achieved in vivo genome editing in adult mouse liver and central nervous system via co-delivery of unformulated, chemically modified crRNAs with protecting oligos and AAV vectors that express tracrRNA and either SpyCas9 or a base editor derivative. Our proof-of-concept establishment of AAV/crRNA co-delivery offers a route towards transient editing activity, target multiplexing, guide redosing, and vector inactivation.
A Community Social Work Paradigm: Thoughts and Reflections
Authors: Weiss-Dagan Shlomit , Aviv Inbal , Eliyahou Ayala , Levy Drorit , Makaros Ayelet , Freiberg Smadar , Zriker Amit
Published: November 2023

Community social work (CSW) is often regarded as a practice with a variety of intervention models. The objectives of the present article are to examine CSW’s philosophical and theoretical roots and to bridge the gap in the literature regarding the theoretical and philosophical origins of CSW and to conceptualize these theoretical bases as a paradigm with ontological, epistemological, axiological, and methodological aspects. The ontology of the proposed CSW paradigm relies on ecological theory, critical theory, and community psychology. The paradigm’s epistemology relies on the basic assumption that community members are autonomous subjective human beings with important and valid knowledge who make decisions concerning their lives. Axiologically, the most prominent value of the paradigm is participation, from which other central values derive. The paradigm’s methodology derives from its three abovementioned components. The conceptualization of a CSW paradigm provides a theoretical foundation for community interventions and refining the goals of these interventions. The paradigm can be used as a pedagogical and identity-building tool with students and social workers who focus on CSW.
Meniscus Tear Requiring Intra-Operative Repair Does Not Influence Mid-term Patient Reported Outcomes in Operatively Treated Tibial Plateau Fractures
Authors: Sato Eleanor H. , O’Neill Dillon C. , Steffenson Lillia N. , Myhre Luke A. , Higgins Thomas F. , Rothberg David L. , Marchand Lucas S. , Haller Justin M.
Published: November 2023

OBJECTIVE:

Evaluate whether intra-operatively repaired lateral meniscus injuries impact mid-term patient reported outcomes in those undergoing operative fixation of tibial plateau fracture.

METHODS:

Design:

Retrospective cohort study.

Setting:

Level I trauma center.

Patient Selection Criteria:

All patients (n=207) who underwent operative fixation of a tibial plateau fracture from 2016-2021 with minimum 10-month follow-up.

Outcome Measures and Comparisons
: The Patient-Reported Outcomes Measurement Information System Physical Function (PROMIS-PF), Knee Injury and Osteoarthritis Outcome Score (KOOS), and the PROMIS-Preference (PROPr) health utility score.

RESULTS:

Overall, 207 patients were included with average follow-up of 2.9 years. Seventy-three (35%) patients underwent intraoperative lateral meniscus repair. Gender, age, body mass index, Charlson Comorbidity Index, days to surgery, ligamentous knee injury, open fracture, vascular injury, polytraumatic injuries, Schatzker classification, and OTA classification were not associated with meniscal repair (p>0.05). Rates of re-operation (42% vs 31%, p=0.11), infection (8% vs 10%, p=0.60), return-to-work (78% vs 75%, p=0.73), and subsequent total knee arthroplasty (8% vs 5%, p=0.39) were also similar between those who had a meniscal repair and those without a meniscal injury, respectively. There was no difference in PROMIS-PF (46.3 vs 45.8, p=0.707), PROMIS-Preference (PROPr) (0.51 vs 0.50, p=0.729), and all KOOS domain scores at final follow-up between those who had a meniscal repair and those without a meniscal injury, respectively.

CONCLUSION:

In patients with an operatively treated tibial plateau fracture, the presence of a concomitant intraoperatively identified and repaired lateral meniscal tear results in similar mid-term PROMs and complication rates when compared to patients without meniscal injury.
Comparison of Fixation Methods between Transosseous Pull-Out Suture and Separate Vertical Wiring for Inferior Pole Fracture of Patella: A Systematic Review and Meta-Analysis
Authors: Kim Kang-Il , Kim Jun-Ho , Son Gwankyu
Published: November 2023

Objectives:

To compare, in a systematic review, Krakow transosseous (KT) suturing and separate vertical wiring (VW) fixation methods in inferior pole fractures of the patella and to evaluate whether the supplementary fixation affected bone union.

Data Sources:

The MEDLINE, Embase, and Cochrane databases were searched from inception to January 15, 2023. The keywords were “patella inferior pole fracture”, “patella distal pole fracture”, “transosseous”, “pull-out suture”, “reattachment”, and “vertical wiring”.

Study Selection:

All clinical studies describing KT or VW techniques for inferior pole fracture of the patella and reporting bone union-related complications were included.

Data Extraction:

This meta-analysis included 16 studies with 274 patellae. Demographic data, surgical techniques, clinical outcomes, and complication rates were recorded. The Methodological Index for Non-Randomized Studies criteria were used to assess their quality.

Data Synthesis:

A meta-analysis was performed using random-effects models and meta-regression. The meta-analytic estimate of bone union-related complications was 3.8% (95% CI, 1.6%-6.0%) for either PO or VW techniques in inferior pole fractures of the patella. The bone union-related complication rates did not differ significantly between the two techniques (KT, 5.7%; VW, 3.0%;P=.277). Meanwhile, supplementation fixation was significantly associated with decrease in bone union-related complication rates (p=.013).

Conclusion:

Fixation of inferior pole fractures of the patella using either KT or VW techniques provided satisfactory and similar clinical results with minimal bone union-related complications. Supplementary fixation has a positive impact on reducing bone union-related complications in inferior pole fractures of the patella following KT and VW techniques.
Three-Dimensional Mapping of Scapular Body, Neck and Glenoid Fractures
Authors: Cole Peter A. , Schroder Lisa K. , Brahme Indraneel S. , Thomas Claire N. , Kuhn Lorenz , Zaehringer Erich , Petersik Andreas
Published: November 2023

Objectives:

The purpose of this study was to report patterns of scapular fractures and define them with a contemporary methodology.

Methods:

Design:

Retrospective study, 2015 – 2021

Setting:

Single, Academic, Level 1 Trauma Center

Patient Selection Criteria:

Consecutive patients ≥ 18 years, presenting with unilateral scapula fracture, with thin-slice (≤ 0.5 mm) bilateral CT scans of the entirety of both the injured and uninjured scapulae

Outcome Measures and Comparisons:

Thin-slice (0.5 mm) computed tomography (CT) scans of injured and normal scapulae were obtained to create three-dimensional (3D) virtual models. 3D modeling software (Stryker Orthopedics Modeling and Analytics, Stryker Trauma GmbH, Kiel, Germany aka SOMA) was used to create a 3D map of fracture location and frequency. Fracture zones were delineated using anatomic landmarks to characterize fracture patterns.

Results:

87 patients were identified with 75 (86%) extra-articular and 12 (14%) intra-articular fractures. The dominant fracture pattern emanated from the superior lateral border (Zone E) to an area inferior to the spinomedial angle (Zone B) and was present in 80% of extra-articular fractures. A second-most common fracture line propagated from the Primary (most-common) Line towards the inferior medial scapular border with a frequency of 36%. Bare zones (with one or no fractures present) were identified in four unique areas. Furthermore, intra-articular fractures were found to be heterogenous.

Conclusions:

The 3D fracture map created in this study confirmed that extra-articular scapular fractures occur in certain patterns with a relatively high frequency. Results provide greater insight into scapular fracture locations and may help to study prognosis of injury and improve treatment strategy including operative approaches and surgical tactics.
The Use of Screening Tests in Differential Diagnosis in Nursing Care
Authors: Búřilová Petra , Melišková Michaela , Búřil Jiří , Haršány Michal , Pokorná Andrea
Published: November 2023

Geriatric syndromes involving instability are associated with a higher risk of further complications in patients with trauma requiring subsequent surgery. Acute stroke symptoms require prompt recognition and initiation of reperfusion treatment. This case study describes the patient's stroke symptoms in a timeline and explores the benefit of objective assessment using screening tests and their importance in the differential diagnosis in nursing. Dysphagia is one of the stroke symptoms that can lead to aspiration pneumonia and increase the risk of mortality. This article aims to inform general nurses about the importance of early recognition of dysphagia and other stroke symptoms using adequate screening tests to ensure quality care. Geriatric syndromes encompass instability, resulting in a higher risk of complications, especially in trauma patients. This case study describes a patient with acute ischemic stroke with vague and unrecognized symptoms of dysphagia and explores the rationale for objective screening tests in nursing care.
Pde5 Inhibition Reduced Blood Pressure and Alleviated Target Organ Damage in Chronic Intermittent Hypoxia
Authors: Li Siyi , Xin Qingjie , Yan Yan , Wang Xiao , Ai Hui , Que Bin , Gong Wei , Nie Shaoping
Published: November 2023

The role of phosphodiesterase 5 (Pde5) in obstructive sleep apnea–induced damage remains unclear. Our study aimed to investigate the role of Pde5 in the chronic intermittent hypoxia (CIH) model. C57BL/6J wild-type (WT) mice (n = 48) and Pde5 knockout (Pde5−/−) mice (n = 24) were randomly assigned to CIH group and room air group. After 6 weeks, some WT mice (n = 24) in CIH group were given sildenafil or saline gavage for another 4 weeks. Blood pressure was regularly measured during the experiment. Echocardiography was used to estimate cardiac function. We collected organs from each group of mice and measured their physical indicators. Histochemical staining was used to explore the size of cardiomyocyte and fibrosis area of various organs. Cyclic guanosine monophosphate and malondialdehyde concentrations in serum were measured by ELISA assay. Compared with the RA-treated group, the 6-week CIH resulted in a significant increase in blood pressure, altered heart structure, and reduced serum cyclic guanosine monophosphate in WT mice. Pde5−/− mice and sildenafil intragastric administration significantly reduced systolic blood pressure in CIH condition and attenuated the damage of target organs. In CIH model, we found that the cardiomyocyte size and fibrosis area of heart and kidney significantly reduced in Pde5−/− groups. Besides, endogenous and exogenous inhibition of Pde5 reduced malondialdehyde level and inflammatory and oxidative stress markers expression in CIH condition. In this study, we found that Pde5 inhibition could reduce blood pressure and alleviate target organ damage in the CIH model, which may be mediated through the oxidative stress pathway.
CK2β Regulates Hematopoietic Stem Cell Biology and Erythropoiesis
Authors: Quotti Tubi Laura , Canovas Nunes Sara , Mandato Elisa , Pizzi Marco , Vitulo Nicola , D’Agnolo Mirco , Colombatti Raffaella , Martella Maddalena , Boaro Maria Paola , Doriguzzi Breatta Elena , Fregnani Anna , Spinello Zaira , Nabergoj Mitja , Filhol Odile , Boldyreff Brigitte , Albiero Mattia , Fadini Gian Paolo , Gurrieri Carmela , Vianello Fabrizio , Semenzato Gianpietro , Manni Sabrina , Trentin Livio , Piazza Francesco
Published: November 2023

The Ser-Thr kinase CK2 plays important roles in sustaining cell survival and resistance to stress and these functions are exploited by different types of blood tumors. Yet, the physiological involvement of CK2 in normal blood cell development is poorly known. Here, we discovered that the β regulatory subunit of CK2 is critical for normal hematopoiesis in the mouse. Fetal livers of conditional CK2β knockout embryos showed increased numbers of hematopoietic stem cells associated to a higher proliferation rate compared to control animals. Both hematopoietic stem and progenitor cells (HSPCs) displayed alterations in the expression of transcription factors involved in cell quiescence, self-renewal, and lineage commitment. HSPCs lacking CK2β were functionally impaired in supporting both in vitro and in vivo hematopoiesis as demonstrated by transplantation assays. Furthermore, KO mice developed anemia due to a reduced number of mature erythroid cells. This compartment was characterized by dysplasia, proliferative defects at early precursor stage, and apoptosis at late-stage erythroblasts. Erythroid cells exhibited a marked compromise of signaling cascades downstream of the cKit and erythropoietin receptor, with a defective activation of ERK/JNK, JAK/STAT5, and PI3K/AKT pathways and perturbations of several transcriptional programs as demonstrated by RNA-Seq analysis. Moreover, we unraveled an unforeseen molecular mechanism whereby CK2 sustains GATA1 stability and transcriptional proficiency. Thus, our work demonstrates new and crucial functions of CK2 in HSPC biology and in erythropoiesis.
CAR-modified Cellular Therapies in Chronic Lymphocytic Leukemia: Is the Uphill Road Getting Less Steep?
Authors: Vitale Candida , Griggio Valentina , Perutelli Francesca , Coscia Marta
Published: November 2023

The clinical development of chimeric antigen receptor (CAR) T-cell therapy has been more challenging for chronic lymphocytic leukemia (CLL) compared to other settings. One of the main reasons is the CLL-associated state of immune dysfunction that specifically involves patient-derived T cells. Here, we provide an overview of the clinical results obtained with CAR T-cell therapy in CLL, describing the identified immunologic reasons for the inferior efficacy. Novel CAR T-cell formulations, such as lisocabtagene maraleucel, administered alone or in combination with the Bruton tyrosine kinase inhibitor ibrutinib, are currently under investigation. These approaches are based on the rationale that improving the quality of the T-cell source and of the CAR T-cell product may deliver a more functional therapeutic weapon. Further strategies to boost the efficacy of CAR T cells should rely not only on the production of CAR T cells with an improved cellular composition but also on additional changes. Such alterations could include (1) the coadministration of immunomodulatory agents capable of counteracting CLL-related immunological alterations, (2) the design of improved CAR constructs (such as third- and fourth-generation CARs), (3) the incorporation into the manufacturing process of immunomodulatory compounds overcoming the T-cell defects, and (4) the use of allogeneic CAR T cells or alternative CAR-modified cellular vectors. These strategies may allow to develop more effective CAR-modified cellular therapies capable of counteracting the more aggressive and still incurable forms of CLL.
Pushing the limits of treatment for hepatocellular carcinoma
Authors: Jones-Pauley Michelle , Victor David W. , Kodali Sudha
Published: November 2023

Purpose of review

We review existing and newer strategies for treatment and surveillance of hepatocellular carcinoma (HCC) both pre and postliver transplantation.

HCC is rising in incidence and patients are often diagnosed at later stages. Consequently, there is a need for treatment strategies which include collaboration of multiple specialties. Combinations of locoregional, systemic, and surgical therapies are yielding better postliver transplantation (post-LT) outcomes for patients with HCC than previously seen. Tumor biology (tumor size, number, location, serum markers, response to therapy) can help identify patients who are at high risk for HCC recurrence posttransplantation and may expand transplant eligibility for some patients.
A narrative review on spontaneous clearance of urogenital Chlamydia trachomatis: Host, microbiome, and pathogen-related factors
Authors: Klasner Carson , Macintyre Andrew N. , Brown Sarah E. , Bavoil Patrik , Ghanem Khalil G. , Nylander Elisabeth , Ravel Jacques , Tuddenham Susan , Brotman Rebecca M.
Published: November 2023

Chlamydia trachomatis (CT) is the most commonly reported sexually transmitted infection in the United States. Untreated urogenital infection in women can result in adverse sequelae such as pelvic inflammatory disease and infertility. Despite national screening and treatment guidelines, rates continue to rise; since most infections are asymptomatic, the actual prevalence of CT infection is likely significantly higher than reported. Spontaneous clearance of CT in women (in the absence of antibiotic treatment) has been described in multiple epidemiologic studies. Given the serious consequences and high prevalence of CT infection, there is growing interest in understanding this phenomenon and factors which may promote CT clearance in women. Spontaneous CT clearance is likely the result of complex interactions between CT, the host immune system, and the vaginal microbiota (i.e., the communities of bacteria inhabiting the vagina) which has been implicated in CT acquisition. Herein, we briefly review current literature regarding the role of each of these factors in spontaneous CT clearance, identify knowledge gaps, and discuss future directions and possible implications for the development of novel interventions which may protect against CT infection, facilitate clearance, and prevent reproductive sequelae.
NUDC is critical for rod photoreceptor function, maintenance, and survival
Authors: Garner Mary Anne , Hubbard Meredith G. , Boitet Evan R. , Hubbard Seth T. , Gade Anushree , Ying Guoxin , Jones Bryan W. , Baehr Wolfgang , Gross Alecia K.
Published: November 2023

NUDC (nucleardistribution protein C) is a mitotic protein involved in nuclear migration and cytokinesis across species. Considered a cytoplasmic dynein (henceforth dynein) cofactor, NUDC was shown to associate with the dynein motor complex during neuronal migration. NUDC is also expressed in postmitotic vertebrate rod photoreceptors where its function is unknown. Here, we examined the role of NUDC in postmitotic rod photoreceptors by studying the consequences of a conditional NUDC knockout in mouse rods (rNudC−/−). Loss of NUDC in rods led to complete photoreceptor cell death at six weeks of age. By 3 weeks of age, rNudC-/-function was diminished, and rhodopsin and mitochondria were mislocalized, consistent with dynein inhibition. Levels of outer segment proteins were reduced, but LIS1 (lissencephaly protein 1), a well-characterized dynein cofactor, was unaffected. Transmission electron microscopy revealed ultrastructural defects within the rods of rNudC−/−by 3 weeks of age. We investigated whether NUDC interacts with the actin modulator cofilin 1 (CFL1) and found that in rods, CFL1 is localized in close proximity to NUDC. In addition to its potential role in dynein trafficking within rods, loss of NUDC also resulted in increased levels of phosphorylated CFL1 (pCFL1), which would purportedly prevent depolymerization of actin. Absence of NUDC also induced an inflammatory response in Müller glia and microglia across the neural retina by 3 weeks of age. Taken together, our data illustrate the critical role of NUDC in actin cytoskeletal maintenance and dynein-mediated protein trafficking in a postmitotic rod photoreceptor.

Significance Statement

Nuclear distribution protein C (NUDC) has been studied extensively as an essential protein for mitotic cell division. In this study, we discovered its expression and role in the postmitotic rod photoreceptor cell. In the absence of NUDC in mouse rods, we detected functional loss, protein mislocalization, and rapid retinal degeneration consistent with dynein inactivation. In the early phase of retinal degeneration, we observed ultrastructural defects and an upregulation of inflammatory markers suggesting additional, dynein-independent functions of NUDC.
Epigenetic reader ZMYND11 noncanonical function restricts HNRNPA1-mediated stress granule formation and oncogenic activity
Authors: Lian Cheng , Zhang Chunyi , Tian Pan , Tan Qilong , Wei Yu , Zhang Qin , Wang Zixian , Zhang Qixiang , Zhong Mengjie , Zhou Li-Quan , Ke Xisong , Zhang Huabing , Zhu Yao , Li Zhenfei , Cheng Jingdong , Wei Gong-Hong
Published: November 2023

ZMYND11 encodes an epigenetic reader of histone methylation, functioning as a transcriptional corepressor. However, whether and how ZMYND11 contributes to cancer progression and therapy remains unclear. Here we report that ZMYND11 downregulation is prevalent in cancers and profoundly correlates with adverse prostate cancer patient outcomes. Depletion of ZMYND11 promotes tumor cell growth, migration and invasionin vitroas well as tumor formation and metastasisin vivo. Mechanistically, we find that ZMYND11 exhibits tumor suppressive roles through recognizing arginine-194-methylated HNRNPA1 dependent on its MYND domain, thereby squeezing HNRNPA1 in nucleus and inhibiting the formation of stress granules in cytoplasm. Furthermore, ZMYND11 antagonizes HNRNPA1-driven high PKM2/PKM1 ratio and counteracts PKM2-induced aggressive tumor phenotype. Remarkably, ZMYND11 recognition of HNRNPA1 could be disrupted by pharmaceutical inhibition of arginine methyltransferase PRMT5 while ZMYND11 low-expressing tumors are sensitive to the treatment of PRMT5 inhibitors. Collectively, our study unravels a novel and noncanonical function of ZMYND11 as the nonhistone methyl reader and discovers a mechanism for the requirement of arginine-methylation-mediated ZMYND11-HNRNPA1 association to restrict tumor progression and offers cancer therapeutic targets and potential biomarkers.
Simulating growth of TDP-43 cytosolic inclusion bodies in neurons
Authors: Kuznetsov Andrey V.
Published: November 2023

This paper introduces a mathematical model for the growth of transactive response DNA binding protein of 43 kDa (TDP-43) inclusion bodies in neuron soma. The model’s equations enable numerical determination of the concentrations of TDP-43 dimers, monomers, and aggregates. Assuming all aggregates integrate into the inclusion bodies, the model predicts the size of TDP-43 inclusion bodies. An approximate solution to the model equations is derived for the scenario in which protein degradation machinery is dysfunctional, resulting in infinite half-lives for TDP-43 dimers, monomers, and aggregates. This solution, valid for large times, predicts that the inclusion body’s radius increases proportionally to the cube root of time. To the best of the author’s knowledge, this study presents the first attempt to model the relationship between the size of TDP-43 inclusion bodies and time. The sensitivity analysis of the approximate solution indicates that the concentrations of TDP-43 monomers and aggregates, as well as inclusion body radii, are independent of the kinetic constants. While the numerical solution of the full mathematical model continues to work with finite half-lives, the approximate solution becomes invalid for scenarios with physiologically relevant (finite) half-lives of TDP-43 dimers, monomers, and aggregates. In contrast to the situation with infinite half-lives, the numerical solution shows that for various values of kinetic constants, the curves representing concentrations of monomers and aggregates, as well as the curves depicting inclusion body radii, converge to distinct constant values.
Neural responses to social cues in the accessory olfactory bulb are altered by context and experience
Authors: Dwyer Joseph , Weinberg Maxwell , Dickinson Sarah Y. , Bergan Joseph
Published: November 2023

Social interaction enhances evolutionary fitness by enabling efficient communication of physiological information between individuals. Semiochemicals, that convey socially relevant physiological information, are detected by the vomeronasal organ (VNO) which projects directly to the accessory olfactory bulb (AOB). Mitral and tufted (M/T) neurons in the AOB convey this information from the AOB to a network of brain regions particularly devoted to processing social information and affecting social behavior. The dynamics of social behaviors are shaped by both context and experience. However, our understanding of how alterations in behavior, triggered by the same social cues, correlate with moment-to-moment fluctuations in neural activity within social circuits remains limited. Here, we investigate how context and experience alter the sensory-driven activity of AOB M/T neurons using fiberphotometry and find that the context in which a stimulus is presented can be as important for determining the strength of response as the identity of the stimulus itself.
Role of Tyrosine Phosphorylation in PTP-PEST
Authors: Sreevidya T S , Manikandan Amrutha , Manoj N , Dixit Madhulika , Vemparala Satyavani
Published: November 2023

We study the influence of tyrosine phosphorylation on PTP-PEST, a cytosolic protein tyrosine phosphatase. Utilizing a combination of experimental data and computational modeling, specific tyrosine sites, notably Y64 and Y88, are identified for potential phosphorylation. Phosphorylation at these sites affects loop dynamics near the catalytic site, altering interactions among key residues and modifying the binding pocket’s size. This, in turn, impacts substrate binding, as indicated by changes in binding energy. Our findings provide insights into the structural and functional consequences of tyrosine phosphorylation on PTP-PEST, enhancing our understanding of its effects on substrate binding and catalytic conformation.
Unraveling the Link between CNVs, General Cognition, and Individual Neuroimaging Deviation Scores from a Reference Cohort
Authors: Fraza Charlotte , Sønderby Ida E. , Boen Rune , Shi Yingjie , Beckmann Christian F. , Marquand Andre F.
Published: November 2023

Copy number variations (CNVs) are genetic variants that can have a substantial influence on neurodevelopment, neuropsychiatric traits, and morphometric brain changes, yet their impact at the individual level remains unknown. Common case-control approaches for analyzing CNVs suffer from limitations: they are unable to inform on individual variation between carriers and preclude the study of rarer variants, due to their limited sample size. This cross-sectional study aims to map individualized brain deviation scores in individuals with pathogenic CNVs. We used normative modeling to map neuroimaging features from several large neuroimaging datasets and applied these models to understand the neurobiological profile of CNV carriers in the UK Biobank. We highlight the 1q21.1 distal deletion and duplication, as an example of our individual-level normative modeling-CNV approach. Next, we counted the number of extreme deviations for each participant from the mean and centiles of variation from population reference norms, giving us a combined risk score per participant per imaging modality. We show a high degree of heterogeneity between pathogenic CNV carriers in their implicated brain regions. For example, the cerebellum, brainstem, and pallidum show large negative deviations for specific 1q21.1 duplication carriers. For certain 1q21.1 deletion CNV carriers the caudate and accumbens show notable positive deviations. Finally, we show that negative deviations from these models are correlated to cognitive function. This study marks a starting point in understanding the impact of pathogenic CNVs on brain phenotypes, underscoring the intricacies of these genetic variations at the individual level and providing a means to study the effects of rare CNVs in carrier individuals.
Primary exposure to Zika virus increases risk of symptomatic dengue virus infection with serotypes 2, 3, and 4 but not serotype 1
Authors: Zambrana Jose Victor , Hasund Chloe M. , Aogo Rosemary A. , Bos Sandra , Arguello Sonia , Gonzalez Karla , Collado Damaris , Miranda Tatiana , Kuan Guillermina , Gordon Aubree , Balmaseda Angel , Katzelnick Leah , Harris Eva
Published: November 2023

Infection with any of the four dengue virus serotypes (DENV1-4) can protect against or enhance subsequent dengue depending on pre-existing antibodies and the subsequent infecting serotype. Additionally, primary infection with the related flavivirus Zika virus (ZIKV) has been shown to increase DENV2 disease. Here, we measured how prior DENV and ZIKV immunity influenced risk of disease caused by all four serotypes in a pediatric Nicaraguan cohort. Of 3,412 participants in 2022, 10.6% experienced symptomatic DENV infections caused by DENV1 (n=139), DENV4 (n=133), DENV3 (n=54), DENV2 (n=9), or an undetermined serotype (n=39). Longitudinal clinical and serological data were used to define infection histories, and generalized linear and additive models adjusted for age, sex, time since the last infection, cohort year, and repeat measurements were used to predict disease risk. Compared to flavivirus-naïve participants, primary ZIKV infection increased disease risk of DENV4 (relative risk = 2.62, 95% confidence interval: 1.48-4.63) and DENV3 (2.90, 1.34-6.27) but not DENV1 (1.20, 0.72-1.99). Primary DENV infection or a DENV followed by ZIKV infection also increased DENV4 risk. We re-analyzed 19 years of cohort data and demonstrated that prior flavivirus-immunity and pre- existing antibody titer differentially affected disease risk for incoming serotypes, increasing risk of DENV2 and DENV4, protecting against DENV1, and protecting at high titers but enhancing at low titers against DENV3. We thus find that prior ZIKV infection, like prior DENV infection, increases risk of certain DENV serotypes. Cross-reactivity among flaviviruses should be carefully considered when assessing vaccine safety and efficacy.

One-Sentence Summary

Dengue disease risk is differentially modulated depending on pre- existing immunity to dengue and Zika virus infections and the secondary infecting serotype.
A systematic review of Flotation-Restricted Environmental Stimulation Therapy (REST)
Authors: Lashgari Elnaz , Chen Emma , Gregory Jackson , Maoz Uri
Published: November 2023

Background

Restricted Environmental Stimulation Therapy (REST) is a therapeutic technique that involves immersing an individual in an environment with minimal sensory input or stimulation. The goal of REST is to induce a state of relaxation that is deeper than what can be achieved through other forms of relaxation techniques. Research suggests that REST can help reduce anxiety, alleviate chronic pain, improve sleep, and enhance creativity and cognitive function. Flotation-REST is a popular type of REST that utilizes an enclosed tank filled with buoyant saltwater to facilitate relaxation. This study aimed to synthesize the evidence on studies that investigate the effects of flotation-REST.

Methods

We used PRISMA to survey the flotation-REST literature from 1960 to 2023. This search was conducted on 29 January 2023 within the Google Scholar and PubMed databases. Journal and conference papers, as well as electronic preprints, that used flotation-REST in their methods, were written in English, and were published in or after 1960 were included; non-original research papers (e.g., review papers, book chapters, and papers solely on types of REST other than flotation-REST (e.g., chamber-REST) were excluded. From each eligible paper, we extracted information regarding the participant sample, application of flotation-REST, experimental design, treatment delivery method, questionnaires and tools, and study results.

Results

In total, we found 60 studies that included 1,838 participants. We propose that the application of flotation-REST can be divided into nine main categories: pain, athletic performance, physiology, stress, consciousness, psychology, creativity, clinical anxiety, sleep, smoking cessation, and other miscellaneous applications. In general, flotation-REST was found to bring about positive effects on pain, athletic performance, stress, mental well-being, and clinical anxiety, while having limited to no effect on sleep-related disorders and smoking cessation.

Conclusion

This paper provides a comprehensive overview of the current research on flotation-REST, highlights ongoing limitations in the literature, and outlines potential areas for future research. While flotation-REST appears to induce various benefits for physical and mental well-being, particularly when it comes to managing states like pain and stress, more research is needed to better understand the mechanisms underlying these effects and to identify optimal treatment protocols for different populations. A limitation of this paper is the relatively small number of studies available for review, which limits the generalizability of certain findings and highlights the need for additional research in this area.
Abundance of human T-cell epitopes in microbial proteomes
Authors: Kovaleva Vasilisa A. , Zvyagin Ivan V.
Published: November 2023

Molecular mimicry, the structural similarity between self and foreign antigens, is considered as a key factor in post-infectious autoimmunity. While certain examples of molecular mimicry are well studied, a comprehensive analysis of its prevalence and impact on the type of T cell response to such self is absent. In this work, we comprehensively studied the frequency of molecular mimicry between human and microbial T-cell epitopes. We performed anin silicoanalysis of the occurrence of T-cell epitopes originating from different sets of proteins: normal self epitopes, proteins involved in autoimmunity, and cancer neoantigens, in the proteomes of commensal and pathogenic microbiota. We show a significant overlap between repertoires of human T-cell epitopes and predicted epitopes from proteins of both commensal and pathogenic microbiota: the counterparts for over 90% of human HLA-I and 5% of HLA-II ligands were found in the microbial proteomes. HLA-II epitopes derived from the proteins involved in autoimmunity were more frequent in microbiota compared to normal self, suggesting a potential deleterious effect of molecular mimicry, while we did not observe this effect for HLA-I epitopes. Cancer epitopes were less frequent in microbiota compared to normal self of epitopes, implicating potential cancer escape from cross-reactive T cells specific to microbial antigens. Together, our results show that molecular mimicry might have a general pro-inflammatory effect on similar self epitopes, though much in this field remains to be explored.
Fractal complexity of Escherichia coli nutrient transport channels is influenced by cell shape and growth environment
Authors: Bottura Beatrice , Rooney Liam , Feeney Morgan , Hoskisson Paul A. , McConnell Gail
Published: November 2023

Recent mesoscopic characterisation of nutrient-transporting channels inE. colihas allowed the identification and measurement of individual channels in whole mature biofilms. However, their complexity under different physiological and environmental conditions remains unknown. Analysis of confocal micrographs of biofilms formed by cell shape mutants ofE. colishows that channels have a high fractal complexity, regardless of cell phenotype or growth medium. In particular, biofilms formed by the mutant strain ΔompR, which has a wide-cell phenotype, have a higher fractal dimension when grown on rich medium than when grown on minimal medium, with channel complexity affected by glucose and agar concentration in the medium. Osmotic stress leads to a dramatic reduction in ΔompRcell size, but has a limited effect on channel morphology. This work shows that fractal image analysis is a powerful tool to quantify the effect of phenotypic mutations and growth environment on the morphological complexity of internalE. colibiofilm structures. If applied to a wider range of mutant strains, this approach could help elucidate the genetic determinants of channel formation inE. colibiofilms.
Glycodiversification of gentamicins throughin vivoglycosyltransferase swapping enabled the creation of novel hybrid aminoglycoside antibiotics with potent activity and low ototoxicity
Authors: Jian Xinyun , Wang Cheng , Wu Shijuan , Sun Guo , Huang Chuan , Qiu Chengbing , Liu Yuanzheng , Leadlay Peter F. , Liu Dong , Deng Zixin , Zhou Fuling , Sun Yuhui
Published: November 2023

Aminoglycosides (AGs) are a class of potent antibiotics with a broad spectrum of activity. However, their use is limited by safety concerns associated with nephrotoxicity and ototoxicity, as well as drug resistance. To address these issues, semi-synthetic approaches for modifying natural AGs have successfully generated new generations of AGs, however, with limited types of modification due to significant challenges in synthesis. This study explores a novel approach that harness the bacterial biosynthetic machinery of gentamicins and kanamycins to create hybrid AGs, installing extensive natural modifications from gentamicins onto kanamycins. This was achieved by glycodiversification of gentamicins via swapping the glycosyltransferase (GT) in their producer with the GT from kanamycins biosynthetic pathway and resulted in the creation of a series of novel AGs with combined structural features of two, therefore referred to as genkamicins (GKs). The manipulation of the hybrid metabolic pathway enabled the target accumulation of different GK species and the successful isolation and characterization of six GK components. These compounds display retained antimicrobial activity against a panel of World Health Organization (WHO) critical priority pathogens, and GK-C2a, in particular, demonstrates low ototoxicity compared to clinical drugs in zebrafish embryos. This study provides a new strategy for diversifying the structure of AGs and a potential avenue for developing less toxic AG drugs to combat infectious diseases.
Validation of a heat-inducibleIxodes scapularisHSP70 promoter and developing a tick-specific 3xP3 promoter sequence in ISE6 cells
Authors: Pham Michael , Hoffmann Hans-Heinrich , Kurtti Timothy J. , Chana Randeep , Garcia-Cruz Omar , Aliabadi Simindokht , Gulia-Nuss Monika
Published: November 2023

Ixodes scapularisis an important vector of many pathogens, including the causative agent of Lyme disease, tick-borne encephalitis, and anaplasmosis. The study of gene function inI. scapularisand other ticks has been hampered by the lack of genetic tools, such as an inducible promoter to permit temporal control over transgenes encoding protein or double-stranded RNA expression. Studies of vector-pathogen relationships would also benefit from the capability to activate anti-pathogen genes at different times during pathogen infection and dissemination. We have characterized an intergenic sequence upstream of the heat shock protein 70 (HSP70) gene that can driveRenillaluciferase expression and mCherry fluorescence in theI. scapulariscell line ISE6. In another construct, we replaced theDrosophila melanogasterminimal HSP70 promoter in the synthetic 3xP3 promoter with a minimal portion of theI. scapularisHSP70 promoter and generated anI. scapularisspecific 3xP3 (Is3xP3) promoter. Both promoter constructs, IsHSP70 and Is3xP3, allow for heat-inducible expression of mCherry fluorescence in ISE6 cells with an approximately 10-fold increase in the percentage of fluorescent positive cells upon exposure to a 2 h heat shock. These promoters described here will be valuable tools for gene function studies and temporal control of gene expression, including anti-pathogen genes.

Graphical abstract