Key Sites Research Articles

Conformational trajectory of the HIV-1 fusion peptide during CD4-induced envelope opening.

The hydrophobic fusion peptide (FP), a critical component of the HIV-1 entry machinery, is located at the N terminal stretch of the envelope (Env) gp41 subunit 1-3 . The receptor-binding gp120 subunit of Env forms a heterodimer with gp41 and assembles into a trimer, in which FP is accessible for antibody binding 3 . Env conformational changes or "opening" that follow receptor binding result in FP relocating to a newly formed interprotomer pocket at the gp41-gp120 interface where it is sterically inaccessible to antibody 4 . The mechanistic steps connecting the entry-related transition of antibody accessible-to-inaccessible FP configurations remain unresolved. Here, using SOSIP-stabilized Env ectodomains 5 , we visualized atomic-level details of a functional entry intermediate, where partially open Env was bound to receptor CD4, co-receptor mimetic antibody 17b, and FP-targeting antibody VRC34.01, demonstrating that FP remains antibody accessible despite substantial receptor-induced Env opening. We determined a series of structures delineating stepwise opening of Env from its closed state to a newly resolved intermediate and defining downstream re-organizations of the gp120-gp41 interface that ultimately resulted in FP burial in an antibody-inaccessible configuration. Our studies improve our understanding of HIV-1 entry and provide information on entry-related conformation reorganization of a key site of HIV vulnerability to neutralizing antibody.

Fine-tuning weibull distribution parameters in Morocco’s Tarfaya and Tangier wind farms using two-stage swarm optimization

This study assesses the efficacy of particle swarm optimization (PSO) in estimating scale ( c) and shape ( k) parameters of the Weibull distribution model for wind energy forecasting at two key wind farm sites in Morocco— Tarfaya in the south and Tangier in the north, utilizing real wind data from 2022. Employing a novel square frequency error objective function to enhance parameter accuracy, the study adopts a two-stage training approach involving recursive least-square estimation and PSO fine-tuning. Validation with artificial data underscores PSO’s effectiveness under diverse wind conditions. Parameter sensitivity analysis identifies four optimal PSO configurations, with the PSO-4 model exhibiting superior performance. Comparative analysis against traditional and heuristic optimization methods consistently demonstrates PSO-4’s lowest root-mean-square error (RMSE) and mean absolute error (MAE), high coefficients of determination ( R2), and shortest computation time. The research highlights PSO-4 model as a precise and efficient tool for Weibull distribution parameter estimation in wind energy forecasting, showcasing robust convergence across both wind farm sites.

Chronometric data and stratigraphic evidence support discontinuity between Neanderthals and early Homo sapiens in the Italian Peninsula

The process by which Palaeolithic Europe was transformed from a Neanderthal-dominated region to one occupied exclusively by Homo sapiens has proven challenging to diagnose. A blurred chronology has made it difficult to determine when Neanderthals disappeared and whether modern humans overlapped with them. Italy is a crucial region because here we can identify not only Late Mousterian industries, assumed to be associated with Neanderthals, but also early Upper Palaeolithic industries linked with the appearance of early H. sapiens, such as the Uluzzian and the Aurignacian. Here, we present a chronometric dataset of 105 new determinations (74 radiocarbon and 31 luminescence ages) from four key southern Italian sites: Cavallo, Castelcivita, Cala, and Oscurusciuto. We built Bayesian-based chronometric models incorporating these results alongside the relative stratigraphic sequences at each site. The results suggest; 1) that the disappearance of Neanderthals probably pre-dated the appearance of early modern humans in the region and; 2) that there was a partial overlap in the chronology of the Uluzzian and Protoaurignacian, suggesting that these industries may have been produced by different human groups in Europe.

Evaluation of Angiotensin-Converting Enzyme 2 Expression In Vivo with Novel 68Ga-Labeled Peptides Originated from the Coronavirus Receptor-Binding Domain.

Angiotensin-converting enzyme 2 (ACE2) is not only a key to the renin-angiotensin-aldosterone system and related diseases, but also the main entry point on cell surfaces for certain coronaviruses, including severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2. By analyzing the different key binding sites from the receptor-binding domain (RBD) of SARS-CoV and SARS-CoV-2, nine new ACE2-targeting peptides (A1 to A9) were designed, synthesized and connected with a chelator, 1,4,7-triazacyclononane-N,N',N''-triacetic acid (NOTA). NOTA-A1, NOTA-A2, NOTA-A4, NOTA-A5, and NOTA-A8 were successfully labeled with [68Ga]Ga3+ and were used for biological evaluation. [68Ga]Ga-NOTA-A2, [68Ga]Ga-NOTA-A5, and [68Ga]Ga-NOTA-A8 showed specific binding to ACE2 via cell assays, and their binding sites and binding capacity were calculated by molecular docking and molecular dynamics simulations. In tumor-bearing mice, A549 tumors were visualized 60 min postinjection of [68Ga]Ga-NOTA-A2, [68Ga]Ga-NOTA-A5, or [68Ga]Ga-NOTA-A8. These peptides also accumulated in the organs with high-level ACE2 expression, confirmed by immunohistochemical stain. Among them, [68Ga]Ga-NOTA-A5 exhibited the highest tumor uptake and tumor/background ratio, and it successfully tracked the increased ACE2 levels in mice tissues after excessive Losartan treatment. In a first-in-human study, the distribution of [68Ga]Ga-NOTA-A5 was evaluated with positron emission tomography/computed tomography (PET/CT) in three participants without adverse events. 68Ga-labeled peptides originated from the coronavirus RBD, with [68Ga]Ga-NOTA-A5 as a typical representative, seem to be safe and effective for the evaluation of ACE2 expression in vivo with PET/CT, facilitating further mechanism investigation and clinical evaluation of ACE2-related diseases.

Strategies of Social Persuasion Against Hussitism

This contribution investigates the different strategies and methods of cultural and social persuasion against the Hussite reformation employed by an important member of the University of Vienna, Peter of Pirchenwart (d. 1436). During his career he used various oral and written means against the “new” heresy: sermons to the people, university lectures, theological commentaries, and short treatise. Different types of audiences were targeted in two cultural centres and key sites of anti-Hussite propaganda in the city of Vienna: the Faculty of Theology and St Stephen’s Church, both connected to the Ducal Court. Here I am going to discuss five unedited texts produced by him: the commentary on the Book IV of the Sentences; the biblical commentary on the Gospel of John, containing two anti-heretic sections, one of which is known to the catalogues under the eloquent title of De religione militari contra Hussitas; the short treatise Determinatio contra Hussitas; and two sermons delivered in 1423 and 1431. In these texts, the dimension of violence (both verbal and physical) is present as a recurring motif and substantial theme; one of Pirchenwart’s primary aims, in fact, is precisely to justify the extermination of heretics, without any form of negotiation or dialogue. Through these case studies I will highlight some of the ways in which the heresy was addressed locally (the city of Vienna), at the intersection of intellectual production and the construction of the collective imaginary.

The stripe rust effector Pst3180.3 inhibits the transcriptional activity of TaMYB4L to modulate wheat immunity and analyzes the key active sites of the interaction conformation

Puccinia striiformis f. sp. tritici (Pst) has a wide range and serious damage, which severely threatens global wheat production. In this study, we focused on an effector protein Pst3180.3, which was induced to be highly expressed during the Pst infection stage. The N-terminal 19 amino acid of Pst3180.3 was verified to function as a signal peptide and transferred to cytoplasm and nucleus of wheat following Pst infection. Transient overexpression of Pst3180.3 in Nicotiana benthamiana inhibited programmed cell death triggered via BAX. The instantaneous silencing of Pst3180.3 by BSMV- HIGS significantly reduced the number of uredinia and increased accumulation of reactive oxygen species. Those results indicated that Pst3180.3 is an important pathogenic factor of Pst. Interaction of Pst3180.3 with a transcription factor TaMYB4L in host was confirmed through yeast two-hybrid, luciferase complementation, and co-immunoprecipitation. Virus-induced gene silencing of TaMYB4L weakened the resistance to Pst, indicated that TaMYB4L may be involved in the positive regulation of plant immunity. Dual-luciferase assays revealed that Pst3180.3 inhibited the transcriptional activity of TaMYB4L. Meanwhile, molecular docking analysis identified the key residue sites for the interaction and binding between Pst3180.3 and MYB4L. Those results demonstrated that Pst3180.3 binds to TaMYB4L and interacts to inhibit wheat resistance to Pst infection.

Sediment dynamics of a major piedmont glacier: the Salzach Glacier in the North Alpine Foreland

Abstract. The foreland basins of the European Alps were repeatedly covered by major piedmont glaciers during Quaternary glacial maxima. The Salzach Glacier was the easternmost of a series of large Pleistocene piedmont glaciers entering the North Alpine Foreland through major Alpine valleys. It covered an area of more than 1000 km2 during at least four glacial maxima. The slightly elevated molasse bedrock provides a high potential for preservation of glacial landforms and offers an ideal setting to explore the erosional and depositional dynamics of a major glacier piedmont lobe. This field excursion guide leads to some selected key sites representing deposits of glacial advance, relative equilibrium, and ice lobe collapse.

Sumptuary Laws, Gender, and Public Dressing in Early Modern Genoa

Abstract This article explores sumptuary legislation and its enforcement in early modern Genoa. Whereas the sumptuary laws from other early modern Italian city-states partitioned society by social rank, profession, or citizenship, the laws in effect in late sixteenth-century Genoa divided the population only into men and women. Genoa therefore represents a key site for exploring gender difference through dress and adornment. Adopting a gendered, sociological, and material culture framework, this article demonstrates how sumptuary laws informed understandings of gender and gendered practices of dressing. It takes as its point of departure a ledger of sumptuary denouncements for the year 1594, and examines how Genoa’s citizens adhered to, or transgressed the gendered expectations set out by the city’s legislative structures. It argues that while prescriptions for idealized masculine and feminine comportment coloured the content and wording of the law, in daily life a spectrum of gendered identities could be enacted through clothing. This article thus advances discourse on the impact of sumptuary laws on understandings of gender in early modern Italy, and the ways in which masculine and feminine identifications were negotiated through and in dialogue with clothing.

Exploration of 4-tolyl-5-(p-tolyloxymethyl)-4H-1,2,4-triazole thioethers as potent 15-LOX inhibitors supported by in vitro, in silico, MD simulation and DNA binding studies

Inflammation is an intricate process exacerbated by the sequential release of lipid mediators during arachidonic acid metabolism through the LOX and COX pathways. The inhibition of enzymes accountable for the arachidonic acid metabolism is attributed to a synergistic anti-inflammatory impact with a broader spectrum of activity. The present study was concerned with the search for lead 15-LOX inhibitors. A new series of alkyl/aralkyl substituted 4-tolyl-5-(p-tolyloxymethyl)-4H-1,2,4-triazole (6a-h) was designed, synthesized, and characterized to determine their 15-LOX inhibitory potential. The analogue 3-(phenethylthio)-4-tolyl-5-(p-tolyloxymethyl)-4H-1,2,4-triazole (6h) was the most potent with IC50 2.73 ± 0.15 µM while 6g, 6d, 6f, 6c exhibited excellent inhibitory activities with IC50 values between 11.39 ± 0.13 and 14.63 ± 0.17 µM. All analogues maintained > 72 % blood mononuclear cells viability at 0.25 mM concentration during MTT assay. In silico ADME profiles predicted druggability potential. The molecular docking studies disclosed binding free energies of -9.78 to -7.94 kcal/mol and His373 and His378 were majorly involved in π-interactions in all molecules. Van der Waals interactions dominated hydrogen bonding in the stabilization of ligand-receptor complexes. MD simulations and free energy calculations revealed the significance of complexes in stabilizing the biomolecular system and helped in identifying the key active site residues that contributed towards the energetics. Studies against DNA dodecamer displayed minor groove binding and intercalation, suggesting a possible role in modulating DNA-related processes. The results approve the active analogues possessing promising druglike properties and work is in progress on the synthesis of more analogues in search for leads as 15-LOX inhibitors.

Regulatory Effects of Maternal Intake of Microbial-Derived Antioxidants on Colonization of Microbiota in Breastmilk and That of Intestinal Microbiota in Offspring.

In this study, sixteen Sprague Dawley (SD) female rats and eight SD male rats were co-housed to mate. Pregnant SD female rats were fed with a control diet or an MA diet. Breast milk, maternal ileum, and intestinal samples of the offspring were collected at the day of birth and ten days afterwards. The results showed that the impact of MA was more obvious on the microbiota of mature milk (p = 0.066) than on that of colostrum. In addition, MA additive did not significantly affect maternal ileal microbiota, but affected offsprings' colonic microbiota significantly ten days after birth (p = 0.035). From the day of giving birth to ten days afterwards, in addition to the increase in microbial richness and diversity, at genus level, the dominant bacteria of breastmilk changed from Pseudomonas veronii to Bacillus and Lactococcus. Different from breastmilk microbiota, ten days after giving birth, the maternal ileal microbiota and the offsprings' intestinal microbiota were dominated by Lactobacillus. Instead of ileal microbiota, offsprings' colonic microbiota is a key action site of maternal MA additive. Therefore, the current findings have significant implications for the development of maternal feed aimed at modulating the intestinal microbiota of offspring, ultimately leading to improved health outcomes for both mothers and their offspring.

Exploring molecular interactions and ADMET profiles of novel MAO-B inhibitors: toward effective therapeutic strategies for neurodegenerative disorders

BackgroundNeurodegenerative disorders (NDs), primarily affecting the elderly, are marked by complex pathophysiological processes and are projected to become the second leading cause of death. Parkinson’s disease (PD), one of the most common NDs, is characterized by motor impairments due to reduced dopamine levels in the substantia nigra (SN), a crucial midbrain region involved in motor control and reward mechanisms. PD also impacts cognitive functions, potentially leading to depression and sleep disturbances. Recent research highlights the importance of MAO-B inhibitors in PD management, as these enzymes play a critical role in regulating neurotransmitter levels by catalyzing the oxidative deamination of intracellular amines and monoamine neurotransmitters.ResultComputational virtual screening of several quinoline-based ligands against the target protein MAO-B (PDB ID: 1OJA) was performed using molecular docking simulation and ADMET studies to identify promising inhibitors for neurodegenerative disease treatment. The most active hit, Compound PA001, exhibited a MolDock score of − 207.76 kcal/mol. Subsequent investigation of 6-methoxy-2-(4-phenylpiperazin-1-yl)quinoline (Compound PA001) using molecular dynamics (MD) simulations with GROMACS revealed potent inhibition and significant interactions at key active site residues. MD simulations confirmed the stability of the Compound PA001-MAO-B complex under physiological conditions. Additionally, ADMET analysis demonstrated that Compound PA001 possesses favorable drug-like properties, including absorption, distribution, metabolism, excretion, and toxicity profiles. These findings underscore 6-methoxy-2-(4-phenylpiperazin-1-yl)quinoline (Compound PA001) as a promising candidate for developing new MAO-B inhibitors to treat neurodegenerative diseases.ConclusionThe research highlighted 6-methoxy-2-(4-phenylpiperazin-1-yl)quinoline (Compound PA001) as a promising MAO-B inhibitor, exhibiting strong binding affinity, stability, and desirable drug-like characteristics for the treatment of neurodegenerative diseases. Among the top ten molecules, Compound PA001 was selected for molecular dynamics (MD) simulation using GROMACS. The compound showed potent inhibition, significant interactions with key active site residues, and stable complex formation under physiological conditions. ADMET analysis further confirmed its favorable pharmacokinetic profile.

Harnessing the potential of the NALT and BALT as targets for immunomodulation using engineering strategies to enhance mucosal uptake.

Mucosal barrier tissues and their mucosal associated lymphoid tissues (MALT) are attractive targets for vaccines and immunotherapies due to their roles in both priming and regulating adaptive immune responses. The upper and lower respiratory mucosae, in particular, possess unique properties: a vast surface area responsible for frontline protection against inhaled pathogens but also simultaneous tight regulation of homeostasis against a continuous backdrop of non-pathogenic antigen exposure. Within the upper and lower respiratory tract, the nasal and bronchial associated lymphoid tissues (NALT and BALT, respectively) are key sites where antigen-specific immune responses are orchestrated against inhaled antigens, serving as critical training grounds for adaptive immunity. Many infectious diseases are transmitted via respiratory mucosal sites, highlighting the need for vaccines that can activate resident frontline immune protection in these tissues to block infection. While traditional parenteral vaccines that are injected tend to elicit weak immunity in mucosal tissues, mucosal vaccines (i.e., that are administered intranasally) are capable of eliciting both systemic and mucosal immunity in tandem by initiating immune responses in the MALT. In contrast, administering antigen to mucosal tissues in the absence of adjuvant or costimulatory signals can instead induce antigen-specific tolerance by exploiting regulatory mechanisms inherent to MALT, holding potential for mucosal immunotherapies to treat autoimmunity. Yet despite being well motivated by mucosal biology, development of both mucosal subunit vaccines and immunotherapies has historically been plagued by poor drug delivery across mucosal barriers, resulting in weak efficacy, short-lived responses, and to-date a lack of clinical translation. Development of engineering strategies that can overcome barriers to mucosal delivery are thus critical for translation of mucosal subunit vaccines and immunotherapies. This review covers engineering strategies to enhance mucosal uptake via active targeting and passive transport mechanisms, with a parallel focus on mechanisms of immune activation and regulation in the respiratory mucosa. By combining engineering strategies for enhanced mucosal delivery with a better understanding of immune mechanisms in the NALT and BALT, we hope to illustrate the potential of these mucosal sites as targets for immunomodulation.

Identification and molecular mechanism of novel antioxidant peptide from fish sauce: A combined quantum chemistry and molecular simulation

Fish sauce, derived from fermented fish, exhibits a notable antioxidant effect after a six-month fermentation process, and we propose that potential antioxidant peptides were present in the fish sauce. We isolated, purified, and identified potential bioactive antioxidant peptides by using fish sauce fermented for 6 months. Additionally, molecular simulation was employed to investigate the antioxidant action mechanism of these bioactive peptides. The molecular docking results revealed that FS4-1 (MHQLSKK), FS4-2 (VLDNSPER), FS4-3 (MNPPAASIK), FS6-1(VLKQAAAGR), and FS6-2 (SPDVSPRR), could dock with the Keap1 receptor. The primary force (Van der Waals' force and hydrogen bonds) and key sites (GLY509 and ALA510) of Keap1 binding to peptides were determined. The active center was located in the side chain of amino acid Met at positions C7H78 and C7H79. We here identified antioxidant peptides in fish sauce and revealed the antioxidant mechanism through molecular simulations.

Refusing Redress: Debt, Inheritance, and Creation in Rosario FerrÉ’s Sweet Diamond Dust

This article proposes a reading of Rosario Ferré’s Sweet Diamond Dust through the logic of debt, an effort focused on unearthing the ideological preconditions of extraction via debt rather than the mechanism of extraction itself. This seminal Puerto Rican collection has largely been read as a critique of the national romance and its underlying racial, gender, and sexual politics of genealogical inquiry. This article traces this inquiry, yet focuses on inheritance, redress, and property ownership as both central to the national romance and as key sites for the negotiation and contestation of the ideologies central to accumulation via debt. It uses Rosa Luxemburg’s theorisation of ongoing primitive accumulation to understand the continuation of capitalism and its generation of a particular indebted subjectivity, reading Gloria and Titina’s razing of the De la Valle home in the book’s eponymous novella as a complication and negotiation of the constitution of an indebted subjectivity.

A new interpretation of soft-sediment deformation features (SSDs) in the Parktown Formation (lower West Rand Group); the physical processes of deformation during deposition

Abstract In the Parktown Formation of the lower West Rand Group (Witwatersrand Supergroup), remarkably well-preserved soft-sedimentary deformation features (SSDs) occur in a number of locations in three stratigraphic horizons across the Vredefort Mountainland and in key sites in Johannesburg. The SSDs were the inevitable products of static liquefaction during early deposition in the Witwatersrand Basin. The trigger to static liquefaction is interpreted to be autogenic and related to cyclic fluctuations in pore fluid pressure(s) during capped dewatering. Allogenic triggers are not indicated. We suggest that static liquefaction was an integral physical process to sediment deposition on the Parktown Formation offshore platform, but a process not previously recognised as important to the modification of the West Rand Group stratigraphy across the Witwatersrand Basin.

Modification of Regulatory Tyrosine Residues Biases Human Hsp90α in its Interactions with Cochaperones and Clients

The highly conserved Hsp90 chaperones control stability and activity of many essential signaling and regulatory proteins including many protein kinases, E3 ligases and transcription factors. Thereby, Hsp90s couple cellular homeostasis of the proteome to cell fate decisions. High-throughput mass spectrometry revealed 178 and 169 posttranslational modifications (PTMs) for human cytosolic Hsp90α and Hsp90β, but for only a few of the modifications the physiological consequences are investigated in some detail. In this study, we explored the suitability of the yeast model system for the identification of key regulatory residues in human Hsp90α. Replacement of three tyrosine residues known to be phosphorylated by phosphomimetic glutamate and by non-phosphorylatable phenylalanine individually and in combination influenced yeast growth and the maturation of 7 different Hsp90 clients in distinct ways. Furthermore, wild-type and mutant Hsp90 differed in their ability to stabilize known clients when expressed in HepG2 HSP90AA1−/− cells. The purified mutant proteins differed in their interaction with the cochaperones Aha1, Cdc37, Hop and p23 and in their support of the maturation of glucocorticoid receptor ligand binding domain in vitro. In vivo and in vitro data correspond well to each other confirming that the yeast system is suitable for the identification of key regulatory sites in human Hsp90s. Our findings indicate that even closely related clients are affected differently by the amino acid replacements in the investigated positions, suggesting that PTMs could bias Hsp90s client specificity.

Passive bicycle training stimulates epiphyseal bone formation and restores bone integrity independent of locomotor recovery in a rat spinal cord injury model.

It is unknown whether activity-based physical therapy (ABPT) modalities that mobilize the paralyzed limbs improve bone integrity at the highly fracture-prone epiphyseal regions of the distal femur and proximal tibia following severe spinal cord injury (SCI). In this study, 4-mo-old skeletally mature littermate-matched male Sprague-Dawley rats received either SHAM surgery or severe contusion SCI. At 1 wk postsurgery, SCI rats were stratified to undergo no-ABPT, two 20-min bouts/day of quadrupedal bodyweight-supported treadmill training (qBWSTT), or hindlimb passive isokinetic bicycle (cycle) training, 5 days/wk for another 3 wk. We assessed locomotor recovery and plantar flexor muscle mass, tracked cancellous and cortical bone microstructure at the distal femoral and proximal tibial epiphyses using in vivo microcomputed tomography (microCT), and evaluated bone turnover at the tibial epiphysis with histomorphometry. All SCI animals displayed persistent hindlimb paralysis and pervasive muscle atrophy. Over the initial 2 wk, which included 1 wk of no exercise and 1 wk of ABPT acclimation, a similar magnitude of bone loss developed in all SCI groups. Thereafter, cancellous bone loss and cortical bone decrements increased in the SCI no-ABPT group. qBWSTT attenuated this trabecular bone loss but did not prevent the ongoing cortical bone deficits. In comparison, twice-daily cycle training increased the number and activity of osteoblasts versus other SCI groups and restored all bone microstructural parameters to SHAM levels at both epiphyseal sites. These data indicate that a novel passive isokinetic cycle training regimen reversed cancellous and cortical bone deterioration at key epiphyseal sites after experimental SCI via osteoblast-mediated bone anabolic mechanisms, independent of locomotor recovery or increased muscle mass.NEW & NOTEWORTHY This study was the first to assess how quadrupedal bodyweight-supported treadmill training or passive isokinetic bicycle (cycle) training impacts bone recovery at the distal femoral and proximal tibial epiphyses in a rat model of severe contusion spinal cord injury. Our results demonstrate that passive isokinetic cycle training completely restored cancellous and cortical bone microstructural parameters at these sites via osteoblast-mediated bone anabolic actions, independent of locomotor recovery or increased plantar flexor muscle mass.

Unlocking the Biological Enigma: Influence of Host Length and Infection Site on Parasite Abundance in Ompok bimaculatus.

The influence of two key factors, host length and infection site, on the host-parasite interaction in Ompok bimaculatus (Butter catfish) from Mukutmanipur Dam Lake, were investigated. Present study involved 192 specimens of Ompok bimaculatus with varying body lengths, subjected to diverse statistical analyses. One-way analysis of variance (ANOVA) was performed for the parasite numbers for three groups (cestode, nematode and trematode). Subsequently, we conducted one-way permutational multivariate analysis of variance (PERMANOVA) followed by pairwise test to assess parasite numbers across three body sites (intestine, mesentery, and bodycavity), employing the Bray-Curtis index. Additionally, Principal Coordinate Analysis (PCoA) for the same dataset was performed using the same index. Linear regression analysis was performed for the fish length-cestode number, fish length-nematode number, fish length-trematode number and fish length-total parasite number. One-way ANOVA revealed no significant differences in parasite numbers among the three endo-helminth groups (cestode, nematode, and trematode). The results of PERMANOVA revealed significant differences in parasite numbers across the three body sites of the host fishes (groups) (F = 9.41, p = 0.0001). Pairwise tests further demonstrated significant differences between the intestine-mesentery, intestine-body-cavity, and mesentery-body-cavity. Additionally, Principal Coordinate Analysis (PCoA) unveiled a significant relationship between infection site and parasite number. However, linear regression analysis examining the relationship between fish length and parasite abundance indicated no significant associations. Through a detailed exploration of the statistical analyses, we provide insights into the host-parasite interaction, elucidating both established knowledge and novel findings in fish parasitology.

Uncoupling the CRMP2-CaV2.2 Interaction Reduces Pain-Like Behavior in a Preclinical Joint-Pain Model

Osteoarthritis (OA) represents a significant pain challenge globally, as current treatments are limited and come with substantial and adverse side effects. Voltage-gated calcium channels have proved to be pharmacologically effective targets, with multiple Food and Drug Administration-approved CaV2.2 modulators available for the treatment of pain. Although effective, drugs targeting CaV2.2 are complicated by the same obstacles facing other pain therapeutics—invasive routes of administration, narrow therapeutic windows, side effects, and addiction potential. We have identified a key regulator of CaV2.2 channels, collapsin response mediator protein 2, that allows us to indirectly regulate CaV2.2 expression and function. We previously developed a peptidomimetic modulator of collapsin response mediator protein 2, CBD3063, that effectively reverses neuropathic and inflammatory pain without negative side effects by reducing membrane expression of CaV2.2. The potent analgesic properties of CBD3063, combined with the lack of negative side effects, prompted us to assess the efficacy of CBD3063 in a rodent model of OA pain. Here, we demonstrate the intraperitoneal administration of CBD3063 alleviates both evoked and nonevoked behavioral hallmarks of OA pain. Further, we reveal that CBD3063 reduces OA-induced increased neural activity in the parabrachial nucleus, a key supraspinal site modulating the pain experience. Together, these studies suggest that CBD3063 is an effective analgesic for OA pain. PerspectiveDespite the high prevalence of OA pain worldwide, current treatment options remain limited. We demonstrate that CBD3063-mediated disruption of the CaV2.2-collapsin response mediator protein 2 interaction alleviates pain in a preclinical joint pain model, providing a promising basis for the development of new OA pain treatments.

Fervo Showed Fractured Geothermal Works, Now Must Do It Bigger, Cheaper, and Soon

Earlier this year, one of the founders of Fervo Energy announced that the geothermal innovator had reached its “Mitchell moment.” Jack Norbeck, chief technology officer for Fervo, likened a test where it used a pair of fractured wells to create water hot enough to generate electricity to the time when Mitchell Energy adopted slickwater fracturing to economically extract large amounts of gas from the ultratight rock in the Barnett Formation. “We have derisked all those core challenges, we reached the Mitchell Energy moment for geothermal,” Norbeck said. By doing all that and supplying 3.5 MW of electricity to the local grid that powers Google facilities, he announced that the firm’s enhanced geothermal system (EGS), had reached the highest level of technical readiness. Now comes the hard part—proving that technical triumph can be turned into something really big. The Mitchell moment in 1997 is remembered because it led to a series of innovations that allowed hydraulic fracturing and horizontal drilling to add enough oil and gas production to move global markets. What has been learned about fracturing in the decades since allowed oil industry veterans at Fervo to effectively use those tools to do what others had failed to accomplish—create high-volume EGS capable of generating power. One big difference between the moments is that Houston-based Fervo’s next step looks like a leap compared to Mitchell’s. After Mitchell’s moment, no innovation was required to sell shale gas from the Barnett or find the oilfield services needed to develop and produce it. Plus, it could learn from the many other companies working in tight rock plays. Its moment was the culmination of years of innovations by oil and service companies who continued finding ways to build on that advance. The endless arguments over who can claim credit for the innovations behind the Mitchell moment are evidence of the size of that support network. Today, Fervo’s efforts are also supported by the oil industry’s service sector and supply chain. Oil company Devon Energy, drilling contractor Helmerich & Payne, and pressure-pumping specialist Liberty Energy are among its early backers. And Fervo is benefiting from the government-funded research and site-evaluation work at the Utah Frontier Observatory for Research in Geothermal Energy (FORGE) site, which is the key site for geothermal testing funded by the US Department of Energy (DOE). But unlike Mitchell, the path to commercial success will require Fervo and others to show they can create large operations to convert the heat they harvest into a cost-competitive commodity in a fast-changing, highly competitive industry. Sage Geosystems recently was added to the short list of geothermal startups with big projects, signing a deal with Meta to build a 150-MW plant somewhere east of the Rockies. Also high on the list is Eavor whose first commercial project will use its closed-loop heating technology for home heating and electric generation in Germany.