bluuebunny/crossref_metadata_2025 huggingface dataset:
“Test-To-PrEP”: Assessing Reach and Adoption of a New Approach to Increase HIV Testing and PrEP Knowledge Using HIV Self-Test Kit Distribution Through PrEP Clients' Social Networks
Authors: Johnson Ariana L. , Butts Stefani A. , Rodriguez Edda , Craker Lacey , Kanamori Mariano , Doblecki-Lewis Susanne
Published: November 2023

Background:

HIV self-testing (HIVST) can increase the reach of HIV testing. Preexposure prophylaxis (PrEP) clients may be ideal distributors of HIVST kits and PrEP information within their social networks. This study uses the Reach, Effectiveness, Adoption, Implementation, and Maintenance framework to evaluate the distribution of HIVST bundled with PrEP information (“Test-to-PrEP” kits) among egocentric friendship networks of PrEP users.

Methods:

The study was conducted in Miami from November 2021 to March 2022. Enrolled PrEP clients (egos; n = 100) were offered Test-to-PrEP kits for distribution. Egos and Test-to-PrEP kit users completed brief online surveys. Descriptive statistics are reported for participants, their reported network members, and users of the Test-to-PrEP kits. Logistic and Poisson regression assessed the relationship between characteristics of egos, alters, and the distribution of Test-to-PrEP kits.

Results:

The 100 enrolled egos reported a total of 414 alters. Participants received 293 Test-to-PrEP kits for distribution with 47 of the 100 participants distributing at least 1 kit. Of those who scanned the quick-response code and responded to the survey, 16.2% reported no previous HIV test and 38.5% reported no prior knowledge of PrEP; 32.5% reported interest in distributing Test-to-PrEP kits, 3 successfully distributed kits, and 2 initiated PrEP.

Conclusions:

An approach using PrEP clients' social networks can disseminate HIVST bundled with PrEP information to critical populations including individuals lacking knowledge of PrEP or who have never been tested for HIV. Future studies will assess whether this use of network effects can increase reach and efficiency of HIV testing and PrEP information distribution.
Impact of Integrase Strand Transfer Inhibitors on Cognition in the HAILO Cohort
Authors: O'Halloran Jane A. , Parra-Rodriguez Luis , Goss Charles W. , Agarwal Mansi , Cooley Sarah , Wu Kunling , Westerhaus Elizabeth , Presti Rachel , Ances Beau M. , Tassiopoulos Katherine , Erlandson Kristine M. ,   for the ACTG A5322 Study Team
Published: November 2023

Background:

Integrase inhibitors (INSTIs) have been associated with poorer cognition in people with HIV (PWH). We examined the impact of switching to INSTIs on neuropsychological (NP) outcomes in PWH 40 years of age and older.

Methods:

From the AIDS Clinical Trials Group observational cohort study, HAILO, we identified PWH who switched to INSTIs, had ≥2 NP assessments before and at least 1 after switch, and maintained viral suppression while on INSTIs. NP performance was assessed with a composite score (NPZ4) including Hopkins Verbal Learning Test (HVLT-R), Digit Symbol test (DSY), Trail Making A, and Trail Making B, while adjusting for covariates and learning effects. Outcomes changes from preswitch and postswitch periods were estimated using piecewise linear mixed models.

Results:

Among 395 PWH (mean age 54 years, 81% male, 20% Hispanic, and 29% Black) NPZ4 increased preswitch and postswitch. There was no difference in slopes between periods for NPZ4 [preswitch 0.036/year (95% CI: 0.03 to 0.043); postswitch 0.022/year (95% CI: 0.006 to 0.005); P = 0.147]. All tests scores improved preswitch (P < 0.01). Postswitch, Trail Making A and DSY increased (all P < 0.01) without differences in rate of change (all P > 0.05). HVLT-R had a nonsignificant decrease postswitch (P = 0.22), resulting in a significant preswitch vs postswitch difference in slopes (P = 0.03).

Conclusions:

NP performance improved regardless of INSTI use. There was an attenuation of improvement in verbal memory in the postswitch vs preswitch period. The clinical significance of these changes is unclear but, overall, INSTIs did not have a consistent detrimental effect on NP outcomes.
Proteomic assay for rapid characterization ofStaphylococcus aureusantimicrobial resistance directly from blood cultures
Authors: Deforet Francis , Carrière Romain , Dufour Pierre L’Aour , Prat Roxane , Desbiolles Chloé , Cottin Noémie , Reuzeau Alicia , Dauwalder Olivier , Dupieux-Chabert Céline , Tristan Anne , Cecchini Tiphaine , Lemoine Jérôme , Vandenesch François
Published: November 2023

An efficient management of bloodstream infections requires a fast identification of the pathogen and a determination of its antimicrobial resistance profile.Staphylococcus aureusis among the most common pathogen causing bloodstream infection. A prompt characterization of methicillin-resistantStaphylococcus aureus(MRSA) and their aminoglycoside resistance profile is therefore crucial to quickly adapt the treatment and improve clinical outcomes. Among analytical technologies, targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) has emerged as a promising tool to detect resistance mechanisms in clinical samples. Herein we present a rapid proteomic workflow to detect and quantify the most clinically relevant antimicrobial resistance effectors inS. aureus: PBP2a, PBP2c, APH(3’)-III, ANT(4’)-I, and AAC(6’)-APH(2’’), directly from positive blood cultures and in less than 70 minutes. This approach provided 99% sensitivity for PBP2a (n=98/99 strains) detection. Sensitivity was 100% for PBP2c (n=5/5), APH(3’)-III (n=16/16) and ANT(4’)-I (n=20/20), and 94% for AAC(6’)-APH(2’’) (n=16/17). Across the entire collection, 100% specificity was reported for each of the 5 resistance proteins. Additionally, relative quantification of ANT(4’)-I expression allowed to discriminate kanamycin-susceptible and -resistant strains, in strains all harboring theant(4’)-Iagene. The LC-MS/MS method presented herein demonstrates its ability to provide a reliable and in-depth profiling ofS. aureusresistance, directly from positive blood culture and in a short turnaround time, as required in clinical laboratories.
Targeting NRP1 with EG00229 induces neurovascular permeability
Authors: Dragoni Silvia , Brash James T. , Fantin Alessandro , Burridge Charles , Denti Laura , Turowski Patric , Ruhrberg Christiana
Published: November 2023

NRP1 is a therapeutic target for inhibiting vascular endothelial growth factor (VEGF)-induced blood vessel dysfunction. The small molecule EG00229 was designed to inhibit VEGF binding to NRP1 and reduce pathological blood vessel growth. However, it is unknown whether EG00229 could also be used to reduce VEGF164-induced vascular leakage, which often exacerbates ischemic diseases due to VEGF upregulation. Here, we show that prior treatment with EG00229 prevents VEGF164-induced vascular permeability signalling, but, unexpectedly, also find that EG00229 increased rather than inhibited vascular leakage. Thus, EG00229 increased vascular leakage either when added alone or concurrently with VEGF164, both in perfused retinal explants and across primary brain EC monolayers. This EG00229-induced vascular leakage was not an off-target effect, because it relied on endothelial NRP1 expression and NRP1’s VEGF164 binding pocket, yet was independent of VEGFR1 and VEGFR2. Moreover, EG00229 activated molecular events typical of VEGF164-induced paracellular permeability, including p38 MAP kinase (p38) and SRC family kinase (SFK) phosphorylation as well as CDH5 rearrangement in endothelial junctions. Investigating EG00229-induced signalling therefore helps elucidate NRP1-dependent mechanisms of paracellular permeability induction and might help identifying new approaches to modulate the neurovascular barrier.
A high-density diffuse optical tomography dataset of naturalistic viewing
Authors: Sherafati Arefeh , Bajracharya Aahana , Jones Michael S. , Speh Emma , Munsi Monalisa , Lin Chen-Hao P. , Fishell Andrew K. , Hershey Tamara , Eggebrecht Adam T. , Culver Joseph P. , Peelle Jonathan E.
Published: November 2023

Traditional laboratory tasks offer tight experimental control but lack the richness of our everyday human experience. As a result many cognitive neuroscientists have been motivated to adopt experimental paradigms that are more natural, such as stories and movies. Here we describe data collected from 58 healthy adult participants (aged 18–76 years) who viewed 10 minutes of a movie (The Good, the Bad, and the Ugly, 1966). Most (36) participants viewed the clip more than once, resulting in 106 sessions of data. Cortical responses were mapped using high-density diffuse optical tomography (first-through fourth nearest neighbor separations of 1.3, 3.0, 3.9, and 4.7 cm), covering large portions of superficial occipital, temporal, parietal, and frontal lobes. Consistency of measured activity across subjects was quantified using intersubject correlation analysis. Data are provided in both channel format (SNIRF) and projected to standard space (NIfTI), using an atlas-based light model. These data are suitable for methods exploration as well as investigating a wide variety of cognitive phenomena.
Do chemical language models provide a better compound representation?
Authors: Torrisi Mirko , Asadollahi Saeid , Vega de León Antonio de la , Wang Kai , Copeland Wilbert
Published: November 2023

In recent years, several chemical language models have been developed, inspired by the success of protein language models and advancements in natural language processing. In this study, we explore whether pre-training a chemical language model on billion-scale compound datasets, such as Enamine and ZINC20, can lead to improved compound representation in the drug space. We compare the learned representations of these models with the de facto standard compound representation, and evaluate their potential application in drug discovery and development by benchmarking them on biophysics, physiology, and physical chemistry datasets. Our findings suggest that the conventional masked language modeling approach on these extensive pre-training datasets is insufficient in enhancing compound representations. This highlights the need for additional physicochemical inductive bias in the modeling beyond scaling the dataset size.
Dissecting Multiparametric Cerebral Hemodynamics using Integrated Ultrafast Ultrasound and Multispectral Photoacoustic Imaging
Authors: Chen Haoyang , Mirg Shubham , Gaddale Prameth , Agrawal Sumit , Li Menghan , Nguyen Van , Xu Tianbao , Li Qiong , Liu Jinyun , Tu Wenyu , Liu Xiao , Drew Patrick J. , Zhang Nanyin , Gluckman Bruce J. , Kothapalli Sri-Rajasekhar
Published: November 2023

Understanding brain-wide hemodynamic responses to different stimuli at high spatiotemporal resolutions can help study neuro-disorders and brain functions. However, the existing brain imaging technologies have limited resolution, sensitivity, imaging depth and provide information about only one or two hemodynamic parameters. To address this, we propose a multimodal functional ultrasound and photoacoustic (fUSPA) imaging platform, which integrates ultrafast ultrasound and multispectral photoacoustic imaging methods in a compact head-mountable device, to quantitatively map cerebral blood volume (CBV), cerebral blood flow (CBF), oxygen saturation (SO2) dynamics as well as contrast agent enhanced brain imaging with high spatiotemporal resolutions. After systematic characterization, the fUSPA system was applied to quantitatively study the changes in brain hemodynamics and vascular reactivity at single vessel resolution in response to hypercapnia stimulation. Our results show an overall increase in brain-wide CBV, CBF, and SO2, but regional differences in singular cortical veins and arteries and a reproducible anti-correlation pattern between venous and cortical hemodynamics, demonstrating the capabilities of the fUSPA system for providing multiparametric cerebrovascular information at high-resolution and sensitivity, that can bring insights into the complex mechanisms of neurodiseases.
Hippocampal-parietal cortex causal directed connectivity during human episodic memory formation: Replication across three experiments
Authors: Das Anup , Menon Vinod
Published: November 2023

Hippocampus-parietal cortex circuits are thought to play a crucial role in memory and attention, but their neural basis remains poorly understood. We employed intracranial EEG from 96 participants (51 females) to investigate the neurophysiological underpinning of these circuits across three memory tasks spanning verbal and spatial domains. We uncovered a consistent pattern of higher causal directed connectivity from the hippocampus to both lateral parietal cortex (supramarginal and angular gyrus) and medial parietal cortex (posterior cingulate cortex) in the delta-theta band during memory encoding and recall. This connectivity was independent of activation or suppression states in the hippocampus or parietal cortex. Crucially, directed connectivity from the supramarginal gyrus to the hippocampus was enhanced in participants with higher memory recall, highlighting its behavioral significance. Our findings align with the attention-to-memory model, which posits that attention directs cognitive resources toward pertinent information during memory formation. The robustness of these results was demonstrated through Bayesian replication analysis of the memory encoding and recall periods across the three tasks. Our study sheds light on the neural basis of casual signaling within hippocampus-parietal circuits, broadening our understanding of their critical roles in human cognition.
3D single-molecule super-resolution imaging of microfabricated multiscale fractal substrates for self-referenced cell imaging
Authors: Cabriel Clément , Córdova-Castro R. Margoth , Berenschot Erwin , Dávila-Lezama Amanda , Pondman Kirsten , Gac Séverine Le , Tas Niels , Susarrey-Arce Arturo , Izeddin Ignacio
Published: November 2023

Microstructures arrayed over a substrate have shown increasing interest due to their ability to provide advanced 3D cellular models, which open new possibilities for cell culture, proliferation, and differentiation. Still, the mechanisms by which physical cues impact the cell phenotype are not fully understood, hence the necessity to interrogate cell behavior at the highest resolution. However, cell 3D high-resolution optical imaging on such microstructured substrates remains challenging due to their complexity, as well as axial calibration issues. In this work, we address this issue by leveraging the self-referenced characteristics of fractal-like structures, which simultaneously modulate cell growth and serve as axial calibration tools. To this end, we use multiscale 3D SiO2substrates consisting of spatially arrayed octahedral features of a few micrometers to hundreds of nanometers. Through optimizations of both the structures and optical imaging conditions, we demonstrate the potential of these 3D multiscale structures as calibration tools for 3D super-resolution microscopy. We use their intrinsic multiscale and self-referenced nature to simultaneously perform lateral and axial calibrations in 3D single-molecule localization microscopy (SMLM) and assess imaging resolutions. We then utilize these substrates as a platform for high-resolution bioimaging. As proof of concept, we cultivate human mesenchymal stem cells on these substrates, revealing very different growth patterns compared to flat glass. Specifically, the spatial distribution of cytoskeleton proteins is vastly modified, as we demonstrate with 3D SMLM assessment.
Structural determinants of the direct inhibition of GIRK channels by Sigma-1 receptor antagonist
Authors: Liu Chang , Chen I-Shan , Tateyama Michihiro , Kubo Yoshihiro
Published: November 2023

G-protein-gated inward rectifier K+(GIRK) channels play critical roles in the regulation of the excitability of cardiomyocytes and neurons and include GIRK1, GIRK2, GIRK3 and GIRK4 subfamily members. BD1047 dihydrobromide (BD1047) is one of the representative antagonists of multi-functional Sigma-1 receptor (S1R). In the analysis of the effect of BD1047 on the inhibition of Gi-coupled receptors by S1R using GIRK channel as an effector, we observed that BD1047 directly inhibits GIRK current even in the absence of S1R. Thus, we aimed to clarify the effect of BD1047 on GIRK channels and its structural determinants. By electrophysiological recordings inXenopus oocytes, we observed that BD1047 directly inhibited the current of GIRK channels, producing a much stronger inhibition of GIRK4 channels compared to GIRK2. It also inhibited the ACh-induced native GIRK current in isolated rat atrial myocytes. Chimeric and mutagenesis studies of GIRK2 and GIRK4 combining with molecular docking analysis, demonstrate the importance of the Leu77 on the proximal N-terminal cytoplasmic region of GIRK4 for the inhibition by BD1047. The activator of GIRK channel, ivermectin, competed with BD1047 at Leu77 on GIRK4. This study provides us with a novel inhibitor of GIRK channels and information for developing pharmacological treatments for GIRK4 associated diseases.

Key points

Sigma-1 receptor antagonist, BD1047, directly inhibits the current of GIRK channels. It strongly inhibits GIRK4 channels but only weakly inhibits GIRK2.

BD1047 inhibits the ACh-induced GIRK current in isolated rat atrial myocyte.

Leu77 on the proximal N-terminal of GIRK4 is essential for the inhibition by BD1047.

Binding of BD1047 adjacent to Leu77, but not to Leu77Ile, was confirmed by molecular docking analysis.

The activator of GIRK channel, ivermectin, competes with BD1047 at Leu77 on GIRK4.
UV damage induces production of mitochondrial DNA fragments with specific length profiles
Authors: Waneka Gus , Stewart Joseph , Anderson John R. , Li Wentao , Wilusz Jeffrey , Argueso Juan Lucas , Sloan Daniel B.
Published: November 2023

UV light is a potent mutagen that induces bulky DNA damage in the form of cyclobutane pyrimidine dimers (CPDs). In eukaryotic cells, photodamage and other bulky lesions occurring in nuclear genomes (nucDNAs) can be repaired through nucleotide excision repair (NER), where dual incisions on both sides of a damaged site precede the removal of a single-stranded oligonucleotide containing the damage. Mitochondrial genomes (mtDNAs) are also susceptible to damage from UV light, but current views hold that the only way to eliminate bulky DNA damage in mtDNAs is through mtDNA degradation. Damage-containing oligonucleotides excised during NER can be captured with anti-damage antibodies and sequenced (XR-seq) to produce high resolution maps of active repair locations following UV exposure. We analyzed previously published datasets fromArabidopsis thaliana, Saccharomyces cerevisiae, andDrosophila melanogasterto identify reads originating from the mtDNA (and plastid genome inA. thaliana). InA. thalianaandS. cerevisiae, the mtDNA-mapping reads have unique length distributions compared to the nuclear-mapping reads. The dominant fragment size was 26 nt inS. cerevisiaeand 28 nt inA. thalianawith distinct secondary peaks occurring in 2-nt (S. cerevisiae) or 4-nt (A. thaliana) intervals. These reads also show a nonrandom distribution of di-pyrimidines (the substrate for CPD formation) with TT enrichment at positions 7-8 of the reads. Therefore, UV damage to mtDNA appears to result in production of DNA fragments of characteristic lengths and positions relative to the damaged location. We hypothesize that these fragments may reflect the outcome of a previously uncharacterized mechanism of NER-like repair in mitochondria or a programmed mtDNA degradation pathway.
ADP release can explain spatially-dependent kinesin binding times
Authors: Nguyen Trini , Narayanareddy Babu Janakaloti , Gross Steven P. , Miles Christopher E.
Published: November 2023

The self-organization of cells relies on the profound complexity of protein-protein interactions. Challenges in directly observing these events have hindered progress toward understanding their diverse behaviors. One notable example is the interaction between molecular motors and cytoskeletal systems that combine to perform a variety of cellular functions. In this work, we leverage theory and experiments to identify and quantify the rate-limiting mechanism of the initial association between a cargo-bound kinesin motor and a microtubule track. Recent advances in optical tweezers provide binding times for several lengths of kinesin motors trapped at varying distances from a microtubule, empowering the investigation of competing models. We first explore a diffusion-limited model of binding. Through Brownian dynamics simulations and simulation-based inference, we find this simple diffusion model fails to explain the experimental binding times, but an extended model that accounts for the ADP state of the molecular motor agrees closely with the data, even under the scrutiny of penalizing for additional model complexity. We provide quantification of both kinetic rates and biophysical parameters underlying the proposed binding process. Our model suggests that most but not every motor binding event is limited by their ADP state. Lastly, we predict how these association rates can be modulated in distinct ways through variation of environmental concentrations and spatial distances.

Significance Statement

Cytoskeletal-motor assemblies self-organize to achieve cellular functions ranging from delivering intracellular cargoes to generating forces in mitosis. Advancements in single-molecule experiments have revealed immense detail about motor detachment and stepping, but relatively little regarding the attachment process. With newly available spatially parameterized motor binding times from an optical trap, the evaluation of mechanistic models for binding becomes possible. We find that a model limited by both diffusive search and ADP-release best explains the data. The coupled chemo-mechanical nature of this interaction is more malleable than either separately, possibly explaining the rich diversity and regulation observed in cells. More broadly, our study provides a timely vignette on leveraging computations with experiments to understand how geometry and other complexities shape protein-protein interactions.
Environmental enrichment and physical exercise prevent stress-induced behavioral and blood-brain barrier alterationsviaFgf2
Authors: Paton Sam E.J. , Solano José L. , Collignon Adeline , Richer Émanuelle , Coulombe-Rozon François , Dion-Albert Laurence , Binder Luisa Bandeira , Dudek Katarzyna Anna , Cadoret Alice ,   Signature Consortium, Lebel Manon , Ménard Caroline
Published: November 2023

Chronic stress can promote loss of blood-brain barrier (BBB) integrity leading to passage of circulating inflammatory mediators in mood-regulating brain areas and establishment of depressive behaviors. Conversely, neurovascular adaptations favoring resilience to stress exposure remain undetermined. Here, we report that environmental enrichment dampens stress-induced loss of endothelial tight junction protein Claudin-5 (Cldn5) along with anxiety- and depression-like behaviors in mice via an increase in fibroblast growth factor 2 (Fgf2). Treatment of mouse and human endothelial cells with Fgf2 preceding an immune challenge with the proinflammatory cytokine TNFα, elevated after chronic stress and in depression, reduces BBB dysfunction, and altered cell signaling. Coping with voluntary physical exercise also protects the BBB from stress deleterious effects by increasing Fgf2 preventing Cldn5 loss, exacerbated inflammation, and social avoidance. Circulating FGF2 level is linked with depression severity and symptomatology in humans supporting involvement of this growth factor in mood disorders and stress-induced BBB changes.
Generation and characterization of a multi-functional panel of monoclonal antibodies for SARS-CoV-2 research and treatment
Authors: Patterson Lila D. , Dubansky Benjamin D. , Dubansky Brooke H. , Stone Shannon , Kumar Mukesh , Rice Charles D.
Published: November 2023

The Coronavirus disease 2019 (COVID19) pandemic caused by Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) is an ongoing threat to global public health. To this end, intense efforts are underway to develop reagents to aid in diagnostics, enhance preventative measures, and provide therapeutics for managing COVID-19. The recent emergence of SARS-CoV-2 Omicron variants with enhanced transmissibility, altered antigenicity, and significant escape of existing monoclonal antibodies and vaccines underlines the importance of the continued development of such agents. The SARS-CoV-2 spike protein and its receptor binding domain (RBD) are critical to viral attachment and host cell entry and are primary targets for antibodies elicited from both vaccination and natural infection. In this study, mice were immunized with two synthetic peptides (Pep 1 and Pep 2) within the RBD of the original Wuhan SARS-CoV-2, as well as the whole RBD as a recombinant protein (rRBD). Hybridomas were generated and a panel of three monoclonal antibodies, mAb CU-P1-1 against Pep 1, mAb CU-P2-20 against Pep 2, and mAb CU-28-24 against rRBD, were generated and further characterized. These mAbs were shown by ELISA to be specific for each immunogen/antigen. Monoclonal antibody CU-P1-1 has limited applicability other than in ELISA approaches and basic immunoblotting. Monoclonal antibody CU-P2-20 is shown to be favorable for ELISA, immunoblotting, and immunohistochemistry (IHC), however, not live virus neutralization. In contrast, mAb CU-28-24 is most effective at live virus neutralization as well as ELISA and IHC. Moreover, mAb CU-28-24 was active against rRBD proteins from Omicron variants B.2 and B.4/B5 as determined by ELISA, suggesting this mAb may neutralize live virus of these variants. Each of the immunoglobulin genes has been sequenced using Next Generation Sequencing, which allows the expression of respective recombinant proteins, thereby eliminating the need for long-term hybridoma maintenance. The synthetic peptides and hybridomas/mAbs are under the intellectual property management of the Clemson University Research Foundation, and the three CDRs have been submitted as an invention disclosure for further patenting and commercialization.
Rho/ROCK activity tunes cell compartment segregation and differentiation in nephron-forming niches
Authors: Viola John M. , Liu Jiageng , Huang Aria , Grindel Samuel H. , Prahl Louis S. , Hughes Alex J.
Published: November 2023

Controlling the time and place of nephron formationin vitrowould improve nephron density and connectivity in next-generation kidney replacement tissues. Recent developments in kidney organoid technology have paved the way to achieving self-sustaining nephrogenic nichesin vitro. The physical and geometric structure of the niche are key control parameters in tissue engineering approaches. However, their relationship to nephron differentiation is unclear. Here we investigate the relationship between niche geometry, cell compartment mixing, and nephron differentiation by targeting the Rho/ROCK pathway, a master regulator of the actin cytoskeleton. We find that the ROCK inhibitor Y-27632 increases mixing between nephron progenitor and stromal compartments in native mouse embryonic kidney niches, and also increases nephrogenesis. Similar increases are also seen in reductionist mouse primary cell and human induced pluripotent stem cell (iPSC)-derived organoids perturbed by Y-27632, dependent on the presence of stromal cells. Our data indicate that niche organization is a determinant of nephron formation rate, bringing renewed focus to the spatial context of cell-cell interactions in kidney tissue engineering efforts.
Plasticity-led and mutation-led evolutions are different modes of the same developmental gene regulatory network
Authors: Ng Eden Tian Hwa , Kinjo Akira R.
Published: November 2023

The standard theory of evolution proposes that mutations cause heritable variations, which are naturally selected, leading to evolution. However, this mutation-led evolution (MLE) is being questioned by an alternative theory called plasticity-led evolution (PLE). PLE suggests that an environmental change induces adaptive phenotypes, which are later genetically accommodated. According to PLE, developmental systems should be able to respond to environmental changes adaptively. However, developmental systems are known to be robust against environmental and mutational perturbations. Thus, we expect a transition from a robust state to a plastic one. To test this hypothesis, we constructed a gene regulatory network (GRN) model that integrates developmental processes, hierarchical regulation, and environmental cues. We then simulated its evolution over different magnitudes of environmental changes. Our findings indicate that this GRN model exhibits PLE under large environmental changes and MLE under small environmental changes. Furthermore, we observed that the GRN model is susceptible to environmental or genetic fluctuations under large environmental changes but is robust under small environmental changes. This indicates a breakdown of robustness due to large environmental changes. Before the breakdown of robustness, the distribution of phenotypes is biased and aligned to the environmental changes, which would facilitate rapid adaptation should a large environmental change occur. These observations suggest that the evolutionary transition from mutation-led to plasticity-led evolution is due to a developmental transition from robust to susceptible regimes over increasing magnitudes of environmental change. Thus, the GRN model can reconcile these conflicting theories of evolution.
The potential effect of romosozumab on perioperative management for instrumentation surgery
Authors: Ishikawa Koji , Tani Soji , Toyone Tomoaki , Tsuchiya Koki , Towatari Tomoko , Oshita Yusuke , Yamamura Ryo , Nagai Takashi , Shirahata Toshiyuki , Inagaki Katsunori , Kudo Yoshifumi
Published: November 2023

Background

Age-related changes in bone health increase the risk for complications in elderly patients undergoing orthopedic surgery. Osteoporosis is a key therapeutic target that needs to be addressed to ensure successful instrumentation surgery. The effectiveness of pharmacological interventions in orthopedic surgery, particularly the new drug romosozumab, is still unknown. We aim to evaluate the effect of 3-month romosozumab treatment on biomechanical parameters related to spinal instrumentation surgery, using the Quantitative Computed Tomography (QCT)-based Finite Element Method (FEM).

Methods

This open-labeled, prospective study included 81 patients aged 60 to 90 years, who met the osteoporosis criteria and were scheduled for either romosozumab or eldecalcitol treatment. Patients were assessed using blood samples, dual-energy absorptiometry (DXA), and QCT. Biomechanical parameters were evaluated using FEM at baseline and 3 months post-treatment. The primary endpoints were biomechanical parameters at 3 months, while secondary endpoints included changes in regional volumetric bone mineral density around the pedicle (P-vBMD) and vertebral body (V-vBMD).

Results

Romosozumab treatment led to significant gains in P-vBMD, and V-vBMD compared to eldecalcitol at 3 months. Notably, the romosozumab group showed greater improvements in all biomechanical parameters estimated by FEM at 3 months compared to the eldecalcitol group.

Conclusion

Romosozumab significantly increased the regional vBMD as well as biomechanical parameters, potentially offering clinical benefits in reducing post-operative complications in patients with osteoporosis undergoing orthopedic instrumentation surgery. This study highlights the novel advantages of romosozumab treatment and advocates further research on its effectiveness in perioperative management.
Neuronal PAS domain 1 identifies a major subpopulation of wakefulness-promoting GABAergic neurons in basal forebrain
Authors: Troppoli Timothy A. , Yang Chun , Katsuki Fumi , Uygun David S. , Lin Ilyan , Aguilar David , Spratt Tristan , Basheer Radhika , McNally James M. , Chan C. Savio , McKenna James T. , Brown Ritchie E.
Published: November 2023

Here we describe a novel group of basal forebrain (BF) neurons expressing neuronal PAS domain 1 (Npas1), a developmental transcription factor linked to neuropsychiatric disorders. Immunohistochemical staining in Npas1-cre-2A-TdTomato mice revealed BF Npas1+neurons are distinct from well-studied parvalbumin or cholinergic neurons. Npas1 staining in GAD67-GFP knock-in mice confirmed that the vast majority of Npas1+neurons are GABAergic, with minimal colocalization with glutamatergic neurons in vGlut1-cre-tdTomato or vGlut2-cre-tdTomato mice. The density of Npas1+neurons was high, 5-6 times that of neighboring cholinergic, parvalbumin or glutamatergic neurons. Anterograde tracing identified prominent projections of BF Npas1+neurons to brain regions involved in sleep-wake control, motivated behaviors and olfaction such as the lateral hypothalamus, lateral habenula, nucleus accumbens shell, ventral tegmental area and olfactory bulb. Chemogenetic activation of BF Npas1+neurons in the light (inactive) period increased the amount of wakefulness and the latency to sleep for 2-3 hr, due to an increase in long wake bouts and short NREM sleep bouts. Non-REM slow-wave (0-1.5 Hz) and sigma (9-15 Hz) power, as well as sleep spindle density, amplitude and duration, were reduced, reminiscent of findings in several neuropsychiatric disorders. Together with previous findings implicating BF Npas1+neurons in stress responsiveness, the anatomical projections of BF Npas1+neurons and the effect of activating them suggest a possible role for BF Npas1+neurons in motivationally-driven wakefulness and stress-induced insomnia. Identification of this major subpopulation of BF GABAergic neurons will facilitate studies of their role in sleep disorders, dementia and other neuropsychiatric conditions involving BF.

SIGNIFICANCE STATEMENT

We characterize a group of basal forebrain (BF) neurons in the mouse expressing neuronal PAS domain 1 (Npas1), a developmental transcription factor linked to neuropsychiatric disorders. BF Npas1+neurons are a major subset of GABAergic neurons distinct and more numerous than cholinergic, parvalbumin or glutamate neurons. BF Npas1+neurons target brain areas involved in arousal, motivation and olfaction. Activation of BF Npas1+neurons in the light (inactive) period increased wakefulness and the latency to sleep due to increased long wake bouts. Non-REM sleep slow waves and spindles were reduced reminiscent of findings in several neuropsychiatric disorders. Identification of this major subpopulation of BF GABAergic wake-promoting neurons will allow studies of their role in insomnia, dementia and other conditions involving BF.
Temporal tau asymmetry spectrum influences divergent behavior and language patterns in Alzheimer’s disease
Authors: Younes Kyan , Smith Viktorija , Johns Emily , Carlson Mackenzie L. , Winer Joseph , He Zihuai , Henderson Victor W. , Greicius Michael D. , Young Christina B. , Mormino Elizabeth C. ,   Alzheimer’s Disease Neuroimaging Initiative Researchers
Published: November 2023

Understanding psychiatric symptoms in Alzheimer’s disease (AD) is crucial for advancing precision medicine and therapeutic strategies. The relationship between AD behavioral symptoms and asymmetry in spatial tau PET patterns is unknown. Braak tau progression implicates the temporal lobes early. However, the clinical and pathological implications of temporal tau laterality remain unexplored.

This cross-sectional study investigated the correlation between temporal tau PET asymmetry and behavior assessed using the neuropsychiatric inventory, and composite scores for memory, executive function, and language; using data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset. In the entire cohort, continuous right and left temporal tau contributions to behavior and cognition were evaluated controlling for age, sex, education, and tau burden on the contralateral side. Additionally, a temporal tau laterality index was calculated to define “asymmetry-extreme” groups (individuals with laterality indices greater than two standard deviations from the mean).

858 individuals (age=73.9±7.7 years, 434(50%) females) were included, comprising 438 cognitively unimpaired (CU) (53.4%) and 420 impaired (CI) participants (48.9%). In the full cohort analysis, right temporal tau was associated with worse behavior (B(SE)=7.19 (2.9),p-value=0.01) and left temporal tau was associated with worse language (B(SE)=1.4(0.2),p-value<0.0001). Categorization into asymmetry-extreme groups revealed 20 right- and 27 left-asymmetric participants. Within these extreme groups, four patterns of tau PET uptake were observed: anterior temporal, typical AD, typical AD with frontal involvement, and posterior.

Asymmetrical tau burden is associated with distinct behavioral and cognitive profiles. Behavioral and socioemotional measures are needed to understand right-sided asymmetry in AD.
Epidemiological Surveillance of Amyotrophic Lateral Sclerosis: A Review
Authors: Wolfson Christina , Gauvin Danielle E. , Ishola Foluso , Oskoui Maryam , Atabe Boris
Published: November 2023

Background

Registries and clinical databases are important tools to systematically record and collect information about individuals with rare diseases and to monitor disease patterns in populations. Through a review of the published literature on strategies used for surveillance of Amyotrophic Lateral Sclerosis (ALS), our objective was to better delineate the varied approaches used to monitor ALS at a population level. Further, we sought to determine the potential of registries to enhance knowledge on the epidemiology of ALS using a case study comparing epidemiological outputs from registries in the United States, United Kingdom, and Italy.

We searched Medline, Embase, Global Health, PsycInfo, Cochrane Library, and CINAHL identifying articles published between January 1st, 2010, and May 12th, 2021. Studies describing population registries, cohorts of individuals with ALS, or large-scale studies aimed at systematically identifying people with ALS, were eligible for inclusion. 1,447 publications were found, of which 141 were selected for full text review, and 41 of those were selected for data extraction. We identified ALS registries and pertinent databases in 4 continents (North America, Europe, Asia, and Oceania). Stated objectives of the registries/databases shaped their framework, methodology, and follow-up. The US National Registry demonstrates substantial research outputs and methodological strengths, producing many descriptive epidemiological outputs (n=5 studies) and several methodological papers (n=12 studies). The UK and Italy overall each produced a similar number of studies (albeit with fewer methodological papers), across several different registries and regions.

Key Messages

Due to challenges inherent to the surveillance of rare diseases, registries are a vital tool in determining and assessing the global impact of ALS. Nevertheless, the development and implementation of registries is not feasible everywhere in the world. There are advantages and drawbacks to structuring registries at a national or regional level, often dictated by funding availability, resources and health care infrastructure, and research objectives. To fully assess the epidemiological burden of ALS globally, collaborative initiatives are needed to fill gaps in knowledge, and there is a critical need to harmonize and optimize the development, collection, and sharing of data across registries.
Estimating cancer risk in carriers of Lynch syndrome variants in UK Biobank
Authors: Fummey Eilidh , Navarro Pau , Plazzer John-Paul , Frayling Ian M , Knott Sara , Tenesa Albert
Published: November 2023

Background

Lynch syndrome (LS) is an inherited cancer predisposition syndrome caused by genetic variants affecting DNA mismatch repair (MMR) genesMLH1,MSH2,MSH6, andPMS2. Cancer risk in LS is estimated from cohorts of individuals ascertained by family history of cancer, which is known to upwardly bias estimates.

Methods

The InSiGHT Database classifies MMR gene variants by pathogenicity through expert panel review of published evidence. 830 carriers of pathogenic or likely pathogenic (path_MMR) MMR gene variants from InSiGHT were identified in 454,756 UK Biobank participants using whole exome sequence. Nelson-Aalen survival analysis was used to estimate cumulative incidence of colorectal, endometrial, and breast cancer.

Results

Cumulative incidence of colorectal and endometrial cancer by age 70 was elevated inpath_MMRcarriers compared to non-carriers (colorectal: 11.8% (95% CI: 9.5 - 14.6) vs. 1.7% (1.6 - 1.7), endometrial: 13.4% (10.2 - 17.6) vs. 1.0% (0.9 - 1.0)), but the magnitude of this increase differed between genes. Cumulative breast cancer incidence by age 70 was not elevated inpath_MMRcarriers compared to non-carriers (8.9% (6.3 - 12.4) vs. 7.5% (7.4 - 7.6)). Cumulative cancer incidence estimates in UK Biobank were similar to estimates from the Prospective Lynch Syndrome Database for all genes and cancers, except there was no evidence for elevated endometrial cancer risk in carriers of pathogenicPMS2variants in UK Biobank.

Conclusion

These results can be used to inform the management of incidentally identified cases of LS. For example, they support the application of existing colorectal cancer surveillance strategies for LS in incidentally identified cases.
Elevated Plasma Complement Factors inCRB1-associated Inherited Retinal Dystrophies
Authors: Moekotte Lude , de Boer Joke H. , Hiddingh Sanne , de Ligt Aafke , Nguyen Xuan-Thanh-An , Hoyng Carel B. , Inglehearn Chris F. , McKibbin Martin , Lamey Tina M. , Thompson Jennifer A. , Chen Fred K. , McLaren Terri L. , AlTalbishi Alaa , Panneman Daan M. , Boonen Erica G.M. , Banfi Sandro , Bocquet Béatrice , Meunier Isabelle , Baere Elfride De , Koenekoop Robert , Ołdak Monika , Rivolta Carlo , Roberts Lisa , Ramesar Raj , Strupaitė-Šileikienė Rasa , Kohl Susanne , Farrar G. Jane , van Vugt Marion , van Setten Jessica , Roosing Susanne , van den Born L. Ingeborgh , Boon Camiel J.F. , van Genderen Maria M. , Kuiper Jonas J.W.
Published: November 2023

Objective

To determine the profile of inflammation-related proteins and complement system factors in serum ofCRB1-associated inherited retinal dystrophies (CRB1-IRDs).

Design

A case-control study.

Subjects, Participants, and/or Controls

A cohort of 30 DutchCRB1-IRD patients and 29 Dutch healthy controls (HC) (Cohort I), and a second cohort of 123CRB1-IRD patients from 14 countries and 1292 controls (Cohort II) were used in this study.

Methods

Quantitative 370-plex targeted proteomics in blood plasma and genotyping of the single nucleotide variant (SNV) rs7535263 in theCFHgene.

Main Outcome Measures

Plasma concentrations of inflammation-related proteins and the genotype of the SNV rs7535263.

Results

CRB1-IRD patients showed increased plasma levels of complement system and coagulation cascade proteins compared to healthy controls. Complement Factor I [CFI], Serpin Family D1 [SERPIND1], and Complement Factor H [CFH] were significantly elevated (q<0.05, adjusted for age and sex), which correlated (Pearson’s correlation coefficient >0.6) with higher levels of plasma Complement Component 3 [C3] (q = 0.064). The most enriched pathway in patients was the “Complement cascade” (R-HSA-166658,Padj=P= 3.03 × 10-15). An analysis of the genotype ofCFHvariant rs7535263, which is in close physical proximity to theCRB1gene and is associated with other retinal conditions by influencing plasma complement levels, revealed significantly skewed allele distribution specifically in Dutch patients (A allele of rs7535263, odds ratio (OR) [95%CI = 2.85 [1.35-6.02],P= 6.19 × 10-3), but not in a global case-control cohort (P= 0.12). However,CRB1missense variants that are common in patients display strong linkage disequilibrium (LD) with rs7535263 inCFHin the UK Biobank (D’ = 0.97 for p.(Cys948Tyr); D’ = 1.0 for p.(Arg764Cys)), indicating that genetic linkage may influence plasma complement factor levels inCRB1-IRD patients. After accounting for theCFHgenotype in the proteomic analyses, we also detected significantly elevated plasma levels of Complement Factor H Related 2 [CFHR2] inCRB1-IRD patients (q = 0.04).

Conclusions

CRB1-IRDs are characterized by changes in plasma levels of complement factors and proteins of the innate immune system, which is influenced by common functional variants in theCFH-CFHRlocus. This indicates that innate immunity is implicated inCRB1-IRDs.
Development of a Liver Disease-Specific Large Language Model Chat Interface using Retrieval Augmented Generation
Authors: Ge Jin , Sun Steve , Owens Joseph , Galvez Victor , Gologorskaya Oksana , Lai Jennifer C. , Pletcher Mark J. , Lai Ki
Published: November 2023

Background

Large language models (LLMs) have significant capabilities in clinical information processing tasks. Commercially available LLMs, however, are not optimized for clinical uses and are prone to generating incorrect or hallucinatory information. Retrieval-augmented generation (RAG) is an enterprise architecture that allows embedding of customized data into LLMs. This approach “specializes” the LLMs and is thought to reduce hallucinations.

Methods

We developed “LiVersa,” a liver disease-specific LLM, by using our institution’s protected health information (PHI)-complaint text embedding and LLM platform, “Versa.” We conducted RAG on 30 publicly available American Association for the Study of Liver Diseases (AASLD) guidelines and guidance documents to be incorporated into LiVersa. We evaluated LiVersa’s performance by comparing its responses versus those of trainees from a previously published knowledge assessment study regarding hepatitis B (HBV) treatment and hepatocellular carcinoma (HCC) surveillance.

Results

LiVersa answered all 10 questions correctly when forced to provide a “yes” or “no” answer. Full detailed responses with justifications and rationales, however, were not completely correct for three of the questions.

Discussions

In this study, we demonstrated the ability to build disease-specific and PHI-compliant LLMs using RAG. While our LLM, LiVersa, demonstrated more specificity in answering questions related to clinical hepatology – there were some knowledge deficiencies due to limitations set by the number and types of documents used for RAG. The LiVersa prototype, however, is a proof of concept for utilizing RAG to customize LLMs for clinical uses and a potential strategy to realize personalized medicine in the future.
Chronotropic Incompetence among People with HIV Improves with Exercise Training in the Exercise for Healthy Aging Study
Authors: Durstenfeld Matthew S. , Wilson Melissa P. , Jankowski Catherine M. , Ditzenberger Grace L. , Longenecker Chris T. , Erlandson Kristine M.
Published: November 2023

Background

People with HIV (PWH) have lower exercise capacity compared to HIV uninfected peers, which may be explained by chronotropic incompetence (CI), the inability to increase heart rate during exercise.

Methods

The Exercise for Healthy Aging Study included adults ages 50-75 with and without HIV. Participants completed 12 weeks of moderate intensity exercise, before randomization to moderate or high intensity for 12 additional weeks. We compared adjusted heart rate reserve (AHRR; CI <80%) on cardiopulmonary exercise testing by HIV serostatus, and change from baseline to 12 and 24 weeks using mixed effects models.

Results

Among 32 PWH and 37 controls (median age 56, 7% female, mean BMI 28 kg/m2), 28% of PWH compared to 11% of controls had CI at baseline (p=0.067). AHRR was lower among PWH (91 vs 102%; difference 11%, 95% CI 2.5-19.7; p=0.01). At week 12, AHRR normalized among PWH (+8%, 95% CI 4-11; p<0.001) and was sustained at week 24 (+5, 95%CI 1-9; p=0.008) compared to no change among controls (95%CI –4 to 4; p=0.95; pinteraction=0.004). After 24 weeks of exercise, only 15% PWH and 10% of controls had CI (p=0.70).

Conclusions

Chronotropic incompetence contributes to reduced exercise capacity among PWH and improves with exercise training.