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Investigations into neuroprotective drugs are in high demand for the treatment of neurodegenerative diseases, such as multiple sclerosis or Alzheimer's disease, but also psychiatric disorders, such as depression, trauma, and substance use. One potential drug class being investigated are tetracyclines impacting on a variety of neuroprotective mechanisms. At the same time, tetracyclines like doxycycline have been suggested to affect human fear and spatial memory as well as reducing declarative memory retention. Based on the assumed necessity for synaptic consolidation in hippocampus-dependent learning, we hypothesised declarative memory may be similarly impaired by doxycycline as fear and spatial memory. Therefore, in this study we investigate the potential diminishing effects of doxycycline on consolidation of declarative memory in healthy humans. Additionally, to test for effect specificity we assessed motor memory, sustained attention, and processing speed. We administered a neuropsychological test battery in three independent randomized placebo-controlled double-blind trials (RCTs), in which healthy young volunteers (total N = 252) either received a single oral dose doxycycline (200 mg, n = 126) or placebo (n = 126) in a between-subject design. We found no evidence for a detrimental effect of doxycycline on declarative memory; instead, doxycycline improved declarative learning (p-value=0.022, Cohen's d=0.15) and memory consolidation (p=0.040, d=0.26). Contrarily, doxycycline slightly reduced motor learning (p=0.001, d=0.10) but subtly strengthened long-term motor memory (p=0.001, d=0.10). These results suggest that doxycycline can improve declarative learning and memory without having long term negative effects on other cognitive domains in healthy humans. Our results give hope to further investigate doxycycline in neuroprotective treatment applications.

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Generalized anxiety disorder is characterized by disruptions in decision-making, including an enhanced aversion to uncertain outcomes (i.e., risk aversion), which is not specific to negative outcomes (i.e., no loss aversion). It is unknown if this uncertainty bias is a trait-like causal factor contributing to anxiety symptoms, or a state-like feature triggered by anxiety symptoms such as worry chains. Here, in-patients with Major Depression Disorder (MDD), with (N = 16) or without (N = 24) Generalized anxiety (GA) symptoms, and healthy controls (N = 23), completed an economic decision-making task before and after worry induction. They were asked to choose between a certain monetary payoff, and an uncertain gamble, allowing for estimation of risk and loss aversion through a computational prospect-theoretic model. There were no significant differences in risk and loss aversion between any of the three groups at baseline. After worry induction, patients with GA symptoms, compared to those without, showed increased risk aversion. This increase was modulated by the severity of anxiety symptoms. These findings suggest that decision-making disruptions in anxiety disorder may be driven by anxiety symptoms such as worry, rather than causing them. This could shape etiological models, motivate standardization of emotional state in research on decision-making in anxiety disorders, support treatment strategies primarily aimed at worry management, and could guide novel interventions focusing on uncertainty exposure across aversive and appetitive domains.

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OBJECTIVE: To establish the pharmacokinetics of the cyclin-dependent kinase-9 inhibitor flavopiridol in equine middle carpal joints, using an extended-release poly lactic-co-glycolic acid (PLGA) microparticle formulation. ANIMALS: 4 healthy horses without evidence of forelimb lameness. METHODS: A 6-week longitudinal pharmacokinetic study was conducted in 2 phases (6 weeks each) in 4 healthy horses. The PLGA microparticles containing 122 µg flavopiridol in 3 mL saline were administered by intra-articular injection into 1 middle carpal joint, with empty PLGA microparticles injected into the contralateral joint as a control. Synovial fluid and plasma were collected at time points out to 6 weeks, and drug concentrations in synovial fluid and plasma were determined using validated protocols. Synovial fluid total protein and total nucleated cell count and differential, CBC, serum biochemistry, and lameness exams were performed at each of the time points. RESULTS: Synovial fluid flavopiridol averaged 19 nM at week 1, gradually reduced to 1.4 nM by 4 weeks, and was generally below the detection limit at 5 and 6 weeks. There was no detectable flavopiridol in the plasma samples, and no adverse effects were observed at any time point. CLINICAL RELEVANCE: Intra-articular injection of PLGA microparticle-encapsulated flavopiridol was well tolerated in horses, with detectable levels of flavopiridol in the synovial fluid out to 4 weeks with negligible systemic exposure. Flavopiridol is a cyclin-dependent kinase-9 inhibitor with potent anti-inflammatory and analgesic activity. The extended-release microparticle formulation promotes intra-articular retention of the drug and it may be an alternative to other intra-articular medications for treatment of equine joint disease.

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Treating flexor tendon injuries within the digital flexor sheath (commonly referred to as palmar hand zone 2) presents both technical and logistical challenges. Success hinges on striking a delicate balance between safeguarding the surgical repair for tendon healing and initiating early rehabilitation to mitigate the formation of tendon adhesions. Adhesions between tendon slips and between tendons and the flexor sheath impede tendon movement, leading to postoperative stiffness and functional impairment. While current approaches to flexor tendon repair prioritize maximizing tendon strength for early mobilization and adhesion prevention, factors such as pain, swelling, and patient compliance may impede postoperative rehabilitation efforts. Moreover, premature mobilization could risk repair failure, necessitating additional surgical interventions. Pharmacological agents offer a potential avenue for minimizing inflammation and reducing adhesion formation while still promoting normal tendon healing. Although some systemic and local agents have shown promising results in animal studies, their clinical efficacy remains uncertain. Limitations in these studies include the relevance of chosen animal models to human populations and the adequacy of tools and measurement techniques in accurately assessing the impact of adhesions. This article provides an overview of the clinical challenges associated with flexor tendon injuries, discusses current on- and off-label agents aimed at minimizing adhesion formation, and examines investigational models designed to study adhesion reduction after intra-synovial flexor tendon repair. Understanding the clinical problem and experimental models may serve as a catalyst for future research aimed at addressing intra-synovial tendon adhesions following zone 2 flexor tendon repair.

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The Late Cretaceous to Paleogene Laramide orogen in the North American Cordillera involved deformation >1,000 km from the plate margin that has been attributed to either plate-boundary end loading or basal traction exerted on the upper plate from the subducted Farallon flat slab. Prevailing tectonic models fail to explain the relative absence of Laramide-aged (ca. 90-60 Ma) contractional deformation within the Cordillera hinterland. Based on Raman spectroscopy of carbonaceous material thermometry and literature data from the restored upper 15-20 km of the Cordilleran crust we reconstruct the Late Cretaceous thermal architecture of the hinterland. Interpolation of compiled temperature data (n = 200) through a vertical crustal column reveals that the hinterland experienced a continuous but regionally elevated, upper-crustal geothermal gradient of >40 °C/km during Laramide orogenesis, consistent with peak metamorphic conditions and synchronous peraluminous granitic plutonism. The hot and partially melted hinterland promoted lower crust mobility and crust-mantle decoupling during flat-slab traction.

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Mammary glands define mammals as a group, yet a comprehensive anatomical description of the mammary gland does not exist for almost any mammalian species. In humans, the anatomical and surgical literature provide conflicting and incomplete descriptions of the gross anatomy of the breast. We dissected 9 male and 15 female human body donors to clarify this gross anatomy. We found that, like other epidermally derived glands of the body, the mammary glandular tissue is constrained to a membrane-bound, central structure referred to as the corpus mammae in the surgical literature, and not dispersed throughout the breast as typically described in the anatomical literature. The major fasciae of the human anterior body wall, including the superficial fatty Camper's fascia and the deeper membranous Scarpa's fascia, both contribute to the structure of the breast. This anatomical arrangement suggests that, as the mammary gland invaginates posteriorly from the integument during embryological development, the mammary fat pad most likely derives from Camper's fascia, and growth of Scarpa's fascia around this fat pad forms the anterior and posterior lamellae of the breast pocket. Anteriorly, Scarpa's fascia becomes a double layer that creates the surface structure of the breast. Posteriorly, Scarpa's fascia forms a circummammary ligament that (1) stabilizes the breast against the thoracic wall and (2) is continuous with Scarpa's fascia on the rest of the anterior body wall. The suspensory ligaments of the breast represent the typical retinaculae cuti found consistently throughout the human body wall, and do not directly attach to the skin. Instead, these retinaculae attach to the anterior or posterior lamella of Scarpa's fascia.

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Chromosomal inversions may play a central role in speciation given their ability to locally reduce recombination and therefore genetic exchange between diverging populations. We analyzed long- and short-read whole-genome data from sympatric and allopatric populations of 2 Drosophila virilis group species, Drosophila montana and Drosophila flavomontana, to understand if inversions have contributed to their divergence. We identified 3 large alternatively fixed inversions on the X chromosome and one on each of the autosomes 4 and 5. A comparison of demographic models estimated for inverted and noninverted (colinear) chromosomal regions suggests that these inversions arose before the time of the species split. We detected a low rate of interspecific gene flow (introgression) from D. montana to D. flavomontana, which was further reduced inside inversions and was lower in allopatric than in sympatric populations. Together, these results suggest that the inversions were already present in the common ancestral population and that gene exchange between the sister taxa was reduced within inversions both before and after the onset of species divergence. Such ancestrally polymorphic inversions may foster speciation by allowing the accumulation of genetic divergence in loci involved in adaptation and reproductive isolation inside inversions early in the speciation process, while gene exchange at colinear regions continues until the evolving reproductive barriers complete speciation. The overlapping X inversions are particularly good candidates for driving the speciation process of D. montana and D. flavomontana, since they harbor strong genetic incompatibilities that were detected in a recent study of experimental introgression.

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Bone is a complex organic-inorganic composite tissue composed of ∼30% organics and ∼70% hydroxyapatite (HAp). Inspired by this, we used 30% collagen and 70% HAp extracted from natural bone using the calcination method to generate a biomimetic bone composite hydrogel scaffold (BBCHS). In one respect, BBCHS, with a fixed proportion of inorganic and organic components similar to natural bone, exhibits good physical properties. In another respect, the highly biologically active and biocompatible HAp from natural bone effectively promotes osteogenic differentiation, and type I collagen facilitates cell adhesion and spreading. Additionally, the well-structured porosity of the BBCHS provides sufficient growth space for bone marrow mesenchymal stem cells (BMSCs) while promoting substance exchange. Compared to the control group, the new bone surface of the defective location in the B-HA70+Col group is increased by 3.4-fold after 8 weeks of in vivo experiments. This strategy enables the BBCHS to closely imitate the chemical makeup and physical structure of natural bone. With its robust biocompatibility and osteogenic activity, the BBCHS can be easily adapted for a wide range of bone repair applications and offers promising potential for future research and development.

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Fear conditioning, also termed threat conditioning, is a commonly used learning model with clinical relevance. Quantification of threat conditioning in humans often relies on conditioned autonomic responses such as skin conductance responses (SCR), pupil size responses (PSR), heart period responses (HPR), or respiration amplitude responses (RAR), which are usually analyzed separately. Here, we investigate whether inter-individual variability in differential conditioned responses, averaged across acquisition, exhibits a multi-dimensional structure, and the extent to which their linear combination could enhance the precision of inference on whether threat conditioning has occurred. In a mega-analytic approach, we re-analyze nine data sets including 256 individuals, acquired by the group of the last author, using standard routines in the framework of psychophysiological modeling (PsPM). Our analysis revealed systematic differences in effect size between measures across datasets, but no evidence for a multidimensional structure across various combinations of measures. We derive the statistically optimal weights for combining the four measures and subsets thereof, and we provide out-of-sample performance metrics for these weights, accompanied by bias-corrected confidence intervals. We show that to achieve the same statistical power, combining measures allows for a relevant reduction in sample size, which in a common scenario amounts to roughly 24%. To summarize, we demonstrate a one-dimensional structure of threat conditioning measures, systematic differences in effect size between measures, and provide weights for their optimal linear combination in terms of maximal retrodictive validity.

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RATIONALE:  Previous work identified an attenuating effect of the matrix metalloproteinase (MMP) inhibitor doxycycline on fear memory consolidation. This may present a new mechanistic approach for the prevention of trauma-related disorders. However, so far, this has only been unambiguously demonstrated in a cued delay fear conditioning paradigm, in which a simple geometric cue predicted a temporally overlapping aversive outcome. This form of learning is mainly amygdala dependent. Psychological trauma often involves the encoding of contextual cues, which putatively necessitates partly different neural circuits including the hippocampus. The role of MMP signalling in the underlying neural pathways in humans is unknown. METHODS: Here, we investigated the effect of doxycycline on configural fear conditioning in a double-blind placebo-controlled randomised trial with 100 (50 females) healthy human participants. RESULTS: Our results show that participants successfully learned and retained, after 1 week, the context-shock association in both groups. We find no group difference in fear memory retention in either of our pre-registered outcome measures, startle eye-blink responses and pupil dilation. Contrary to expectations, we identified elevated fear-potentiated startle in the doxycycline group early in the recall test, compared to the placebo group. CONCLUSION: Our results suggest that doxycycline does not substantially attenuate contextual fear memory. This might limit its potential for clinical application.

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Pavlovian fear conditioning is widely used as a pre-clinical model to investigate methods for prevention and treatment of anxiety and stress-related disorders. In this model, fear memory consolidation is thought to require synaptic remodeling, which is induced by signaling cascades involving matrix metalloproteinase 9 (MMP-9). Here we investigated the effect of the tetracycline antibiotic minocycline, an inhibitor of MMP-9, on fear memory retention. We conducted a pre-registered, randomized, double-blind, placebo-controlled trial in N = 105 healthy humans (N = 70 female), using a configural fear conditioning paradigm. We administered a single dose of minocycline before configural fear memory acquisition and assessed fear memory retention seven days later in a recall test. To index memory retention, we pre-registered fear-potentially startle (FPS) as our primary outcome, and pupil dilation as the secondary outcome. As control indices of memory acquisition, we analyzed skin conductance responses (SCR) and pupil dilation. We observed attenuated retention of configural fear memory in individuals treated with minocycline compared to placebo, as measured by our primary outcome. In contrast, minocycline did not affect fear memory acquisition or declarative contingency memory. Our findings provide in-vivo evidence for the inhibition of fear memory consolidation by minocycline. This could motivate further research into primary prevention, and given the short uptake time of minocycline, potentially also secondary prevention of PTSD after trauma.

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Psychometrics is historically grounded in the study of individual differences. Consequently, common metrics such as quantitative validity and reliability require between-person variance in a psychological variable to be meaningful. Experimental psychology, in contrast, deals with variance between treatments, and experiments often strive to minimise within-group person variance. In this article, I ask whether and how psychometric evaluation can be performed in experimental psychology. A commonly used strategy is to harness between-person variance in the treatment effect. Using simulated data, I show that this approach can be misleading when between-person variance is low, and in the face of methods variance. I argue that this situation is common in experimental psychology, because low between-person variance is desirable, and because methods variance is no more problematic in experimental settings than any other source of between-person variance. By relating validity and reliability with the corresponding concepts in measurement science outside psychology, I show how experiment-based calibration can serve to compare the psychometric quality of different measurement methods in experimental psychology.

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Animals including humans must cope with immediate threat and make rapid decisions to survive. Without much leeway for cognitive or motor errors, this poses a formidable computational problem. Utilizing fully immersive virtual reality with 13 natural threats, we examined escape decisions in N = 59 humans. We show that escape goals are dynamically updated according to environmental changes. The decision whether and when to escape depends on time-to-impact, threat identity and predicted trajectory, and stable personal characteristics. Its implementation appears to integrate secondary goals such as behavioral affordances. Perturbance experiments show that the underlying decision algorithm exhibits planning properties and can integrate novel actions. In contrast, rapid information-seeking and foraging-suppression are only partly devaluation-sensitive. Instead of being instinctive or hardwired stimulus-response patterns, human escape decisions integrate multiple variables in a flexible computational architecture. Taken together, we provide steps toward a computational model of how the human brain rapidly solves survival challenges.

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All animals have to respond to immediate threats in order to survive. In non-human animals, a diversity of sophisticated behaviours has been observed, but research in humans is hampered by ethical considerations. Here, we present a novel immersive VR toolkit for the Unity engine that allows assessing threat-related behaviour in single, semi-interactive, and semi-realistic threat encounters. The toolkit contains a suite of fully modelled naturalistic environments, interactive objects, animated threats, and scripted systems. These are arranged together by the researcher as a means of creating an experimental manipulation, to form a series of independent "episodes" in immersive VR. Several specifically designed tools aid the design of these episodes, including a system to allow for pre-sequencing the movement plans of animal threats. Episodes can be built with the assets included in the toolkit, but also easily extended with custom scripts, threats, and environments if required. During the experiments, the software stores behavioural, movement, and eye tracking data. With this software, we aim to facilitate the use of immersive VR in human threat avoidance research and thus to close a gap in the understanding of human behaviour under threat.

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Identifying regions of the genome that act as barriers to gene flow between recently diverged taxa has remained challenging given the many evolutionary forces that generate variation in genetic diversity and divergence along the genome, and the stochastic nature of this variation. Progress has been impeded by a conceptual and methodological divide between analyses that infer the demographic history of speciation and genome scans aimed at identifying locally maladaptive alleles i.e. genomic barriers to gene flow. Here we implement genomewide IM blockwise likelihood estimation (gIMble), a composite likelihood approach for the quantification of barriers, that bridges this divide. This analytic framework captures background selection and selection against barriers in a model of isolation with migration (IM) as heterogeneity in effective population size (Ne) and effective migration rate (me), respectively. Variation in both effective demographic parameters is estimated in sliding windows via pre-computed likelihood grids. gIMble includes modules for pre-processing/filtering of genomic data and performing parametric bootstraps using coalescent simulations. To demonstrate the new approach, we analyse data from a well-studied pair of sister species of tropical butterflies with a known history of post-divergence gene flow: Heliconius melpomene and H. cydno. Our analyses uncover both large-effect barrier loci (including well-known wing-pattern genes) and a genome-wide signal of a polygenic barrier architecture.

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Detecting unusual auditory stimuli is crucial for discovering potential threat. Locus coeruleus (LC), which coordinates attention, and amygdala, which is implicated in resource prioritization, both respond to deviant sounds. Evidence concerning their interaction, however, is sparse. Seeking to elucidate if human amygdala affects estimated LC activity during this process, we recorded pupillary responses during an auditory oddball and an illuminance change task, in a female with bilateral amygdala lesions (BG) and in n = 23 matched controls. Neural input in response to oddballs was estimated via pupil dilation, a reported proxy of LC activity, harnessing a linear-time invariant system and individual pupillary dilation response function (IRF) inferred from illuminance responses. While oddball recognition remained intact, estimated LC input for BG was compacted to an impulse rather than the prolonged waveform seen in healthy controls. This impulse had the earliest response mean and highest kurtosis in the sample. As a secondary finding, BG showed enhanced early pupillary constriction to darkness. These findings suggest that LC-amygdala communication is required to sustain LC activity in response to anomalous sounds. Our results provide further evidence for amygdala involvement in processing deviant sound targets, although it is not required for their behavioral recognition.

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Fear conditioning is a laboratory paradigm commonly used to investigate aversive learning and memory. In context fear conditioning, a configuration of elemental cues (conditioned stimulus [CTX]) predicts an aversive event (unconditioned stimulus [US]). To quantify context fear acquisition in humans, previous work has used startle eyeblink responses (SEBRs), skin conductance responses (SCRs), and verbal reports, but different quantification methods have rarely been compared. Moreover, preclinical intervention studies mandate recall tests several days after acquisition, and it is unclear how to induce and measure context fear memory retention over such a time interval. First, we used a semi-immersive virtual reality paradigm. In two experiments (N = 23 and N = 28), we found successful declarative learning and memory retention over 7 d but no evidence of other conditioned responses. Next, we used a configural fear conditioning paradigm with five static room images as CTXs in two experiments (N = 29 and N = 24). Besides successful declarative learning and memory retention after 7 d, SCR and pupil dilation in response to CTX onset differentiated CTX+/CTX- during acquisition training, and SEBR and pupil dilation differentiated CTX+/CTX- during the recall test, with medium to large effect sizes for the most sensitive indices (SEBR: Hedge's g = 0.56 and g = 0.69; pupil dilation: Hedge's g = 0.99 and g = 0.88). Our results demonstrate that with a configural learning paradigm, context fear memory retention can be demonstrated over 7 d, and we provide robust and replicable measurement methods to this end.

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BACKGROUND: Circular RNAs (circRNAs) have risen to prominence as important regulators of biological processes. This study investigated whether circGNB1 functions as a competitive endogenous RNA to regulate the pathological process of oxidative stress in age-related osteoarthritis (OA). METHODS: The relationship between circGNB1 expression and oxidative stress/OA severity was determined in cartilages from OA patients at different ages. The biological roles of circGNB1 in oxidative stress and OA progression, and its downstream targets were determined using gain- and loss-of-function experiments in various biochemical assays in human chondrocytes (HCs). The in vivo effects of circGNB1 overexpression and knockdown were also determined using a destabilization of the medial meniscus (DMM) mouse model. RESULTS: Increased circGNB1 expression was detected in HCs under oxidative and inflammatory stress and in the cartilage of older individuals. Mechanistically, circGNB1 sponged miR-152-3p and thus blocked its interaction with its downstream mRNA target, ring finger protein 219 (RNF219), which in turn stabilized caveolin-1 (CAV1) by preventing its ubiquitination at the K47 residue. CircGNB1 inhibited IL-10 signalling by antagonizing miR-152-3p-mediated RNF219 and CAV1 inhibition. Consequently, circGNB1 overexpression promoted OA progression by enhancing catabolic factor expression and oxidative stress and by suppressing anabolic genes in vitro and in vivo. Furthermore, circGNB1 knockdown alleviated the severity of OA, whereas circGNB1 overexpression had the opposite effect in a DMM mouse model of OA. CONCLUSION: CircGNB1 regulated oxidative stress and OA progression via the miR-152-3p/RNF219/CAV1 axis. Modulating circGNB1 could be an effective strategy for treating OA.

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