A Theoretical Comparison of Alternative Male Mating Strategies in Cephalopods and Fishes.

We used computer simulations of growth, mating and death of cephalopods and fishes to explore the effect of different life-history strategies on the relative prevalence of alternative male mating strategies. Specifically, we investigated the consequences of single or multiple matings per lifetime, mating strategy switching, cannibalism, resource stochasticity, and altruism towards relatives. We found that a combination of single (semelparous) matings, cannibalism and an absence of mating strategy changes in one lifetime led to a more strictly partitioned parameter space, with a reduced region where the two mating strategies co-exist in similar numbers. Explicitly including Hamilton's rule in simulations of the social system of a Cichlid led to an increase of dominant males, at the expense of both sneakers and dwarf males ("super-sneakers"). Our predictions provide general bounds on the viable ratios of alternative male mating strategies with different life-histories, and under possibly rapidly changing ecological situations.

Random matrix model of Kolmogorov-Zakharov turbulence.

We introduce and study a random matrix model of Kolmogorov-Zakharov turbulence in a nonlinear purely dynamical finite-size system with many degrees of freedom. For the case of a direct cascade, the energy and norm pumping takes place at low energy scales with absorption at high energies. For a pumping strength above a certain chaos border, a global chaotic attractor appears with a stationary energy flow through a Hamiltonian inertial energy interval. In this regime, the steady-state norm distribution is described by an algebraic decay with an exponent in agreement with the Kolmogorov-Zakharov theory. Below the chaos border, the system is located in the quasi-integrable regime similar to the Kolmogorov-Arnold-Moser theory and the turbulence is suppressed. For the inverse cascade, the system rapidly enters a strongly nonlinear regime where the weak turbulence description is invalid. We argue that such a dynamical turbulence is generic, showing that it is present in other lattice models with disorder and Anderson localization. We point out that such dynamical models can be realized in multimode optical fibers.

S2k guideline for the treatment of hidradenitis suppurativa / acne inversa - Short version.

The S2k guideline on hidradenitis suppurativa/acne inversa (HS/AI) aims to provide an accepted decision aid for the selection/implementation of appropriate/sufficient therapy. HS/AI is a chronic recurrent, inflammatory, potentially mutilating skin disease of the terminal hair follicle-glandular apparatus, with painful, inflammatory lesions in the apocrine gland-rich regions of the body. Its point prevalence in Germany is 0.3%, it is diagnosed with a delay of 10.0 ± 9.6 years. Abnormal differentiation of the keratinocytes of the hair follicle-gland apparatus and accompanying inflammation form the central pathogenetic basis. Primary HS/AI lesions are inflammatory nodules, abscesses and draining tunnels. Recurrences in the last 6 months with at least 2 lesions at the predilection sites point to HS/AI with a 97% accuracy. HS/AI patients suffer from a significant reduction in quality of life. For correct treatment decisions, classification and activity assessment should be done with a validated tool, such as the International Hidradenitis Suppurativa Severity Scoring System (IHS4). HS/AI is classified into two forms according to the degree of detectable inflammation: active, inflammatory (mild, moderate, and severe according to IHS4) and predominantly inactive, non-inflammatory (Hurley grade I, II and III) HS/AI. Oral tetracyclines or 5-day intravenous therapy with clindamycin are equal to the effectiveness of clindamycin/rifampicin. Subcutaneously administered adalimumab, secukinumab and bimekizumab are approved for the therapy of HS/AI. Various surgical procedures are available for the predominantly non-inflammatory disease form. Drug/surgical combinations are considered a holistic therapy method.

Radiological follow-up of cemento-osseous dysplasia on cone-beam computed tomography.

This study investigated the natural course of cemento-osseous dysplasia (COD) on cone-beam computed tomography (CBCT). Retrospectively, 104 CBCT scans from 36 patients (mean age, 44.5 years; 33 female and three male) with mandibular COD (10 florid, seven focal, 19 periapical) were included, based upon clinico-radiological features, without complications such as infection and related surgery. Changes in maximum diameter and morphology (lytic, mixed lytic-sclerotic, sclerotic) were evaluated in 83 lesions, with a mean follow-up of 28.3 months. The occurrence of a diameter increase was assessed by time-to-event analysis; interreader agreement for diameter and morphological evaluation by intraclass correlation coefficient and weighted κ statistics, respectively. Fifteen of 83 (18.1%) lesions (eight florid, one focal, six periapical) in 10 patients increased in diameter; 12 of 83 (14.5%) lesions (five florid, seven periapical) in 11 patients changed morphologically. The median period until a diameter increase was longest (120 months) for periapical COD, and shortest (66 months) for florid COD (p = 0.023). There was high reader agreement (ICC = 0.891; weighted κ = 0.901). In conclusion, CBCT is an effective tool with which to follow-up COD. If any, the natural progress in uncomplicated COD is prolonged, which underlines its non-surgical character and aids in its long-term management.

Effect of experimentally induced muscle pain on neuromuscular control of force production.

PURPOSE: Neural and peripheral effects of induced muscle pain on explosive force production were investigated. METHODS: Nine participants performed two maximal, six explosive, and six electrical stimulations induced (twitches and octets) isometric knee extensions before and after (15 min of rest) receiving an intramuscular injection of hypertonic saline (pain inducer) or isotonic (placebo) infusions in two laboratory visits separated by 7 days. RESULTS: It was observed a reduction of peak torque production in maximal voluntary contraction in both conditions (9.3 and 3.3% for pain and placebo, respectively) and in the rate of torque development in placebo (7%). There was an increase in the rate of torque development for twitch and octets (10.5 and 15.8%, respectively) in the pain condition and peak torque for twitch (12%) in both conditions (as did the total rate of torque development for octets). CONCLUSION: Force production decreases and increases during voluntary and involuntary contractions, respectively, suggesting that acute pain impairs force production via central mechanisms.

Live-cell biosensors based on the fluorescence lifetime of environment-sensing dyes.

In this work, we examine the use of environment-sensitive fluorescent dyes in fluorescence lifetime imaging microscopy (FLIM) biosensors. We screened merocyanine dyes to find an optimal combination of environment-induced lifetime changes, photostability, and brightness at wavelengths suitable for live-cell imaging. FLIM was used to monitor a biosensor reporting conformational changes of endogenous Cdc42 in living cells. The ability to quantify activity using phasor analysis of a single fluorophore (e.g., rather than ratio imaging) eliminated potential artifacts. We leveraged these properties to determine specific concentrations of activated Cdc42 across the cell.

The Viewing Reaction Time as a Diagnostic Tool of Pedohebephilia in the Dunkelfeld.

Diagnosing pedohebephilia is fraught with obstacles given the tabooed nature of this sexual preference. The viewing reaction time effect (VRT) provides a non-intrusive indirect measure of sexual interest in minors. In forensic populations, the ability of the difference between the latencies while viewing child and adult sexual stimuli (VRT index) to discern child sexual offenders from a range of control groups has been ascertained meta-analytically. Given that the effect has been studied almost exclusively in forensic samples, its dependence or independence on prior overt (deviant) sexual behavior remains unclear. The present study sought to examine the relationship of prior sexual and non-sexual behaviors with the VRT in a sample of 282 self-referring, help-seeking men with and without pedohebephilia with and without a history of prior child sexual offenses (CSO) or a use of child sexual abuse materials (CSAM) recruited outside a forensic context. We found that (1) the clinical diagnosis of pedohebephilia but not prior CSO or CSAM showed a significant association with the VRT index; (2) the discriminatory ability of the VRT index did not differ significantly between samples with and without a history of prior overt sexual behavior with children; (3) the VRT index correlated positively with a behavioral marker of pedohebephilia in a subsample of individuals with prior judicially detected or undetected overt sexual behavior with children; and (4) in the same subsample, the VRT index correlated positively with markers of sexual interests in minors or hypersexuality but not of antisociality. Equivalence testing failed to refute a potential effect of prior sexual behavior on the VRT index. Our study showed that the VRT may provide an unintrusive diagnostic tool for pedohebephilia. The effect of prior overt sexual behavior with children needs further examination.

Goal quest for an intelligent surfer moving in a chaotic flow.

We consider a model of an intelligent surfer moving on the Ulam network generated by a chaotic dynamics in the Chirikov standard map. This directed network is obtained by the Ulam method with a division of the phase space in cells of fixed size forming the nodes of a Markov chain. The goal quest for this surfer is to determine the network path from an initial node A to a final node B with minimal resistance given by the sum of inverse transition probabilities. We develop an algorithm for the intelligent surfer that allows us to perform the quest in a small number of transitions which grows only logarithmically with the network size. The optimal path search is done on a fractal intersection set formed by nodes with small Erdös numbers of the forward and inverted networks. The intelligent surfer exponentially outperforms a naive surfer who tries to minimize its phase space distance to target B. We argue that such an algorithm provides unique hints for motion control in chaotic flows.

The energy challenges of artificial superintelligence.

We argue here that contemporary semiconductor computing technology poses a significant if not insurmountable barrier to the emergence of any artificial general intelligence system, let alone one anticipated by many to be "superintelligent". This limit on artificial superintelligence (ASI) emerges from the energy requirements of a system that would be more intelligent but orders of magnitude less efficient in energy use than human brains. An ASI would have to supersede not only a single brain but a large population given the effects of collective behavior on the advancement of societies, further multiplying the energy requirement. A hypothetical ASI would likely consume orders of magnitude more energy than what is available in highly-industrialized nations. We estimate the energy use of ASI with an equation we term the "Erasi equation", for the Energy Requirement for Artificial SuperIntelligence. Additional efficiency consequences will emerge from the current unfocussed and scattered developmental trajectory of AI research. Taken together, these arguments suggest that the emergence of an ASI is highly unlikely in the foreseeable future based on current computer architectures, primarily due to energy constraints, with biomimicry or other new technologies being possible solutions.

Imaging the Posterior Elements of the Spine.

The posterior elements of the spine consist of the pedicles, laminae, facets (articular processes), transverse processes, and the spinous process. They are essential for spinal stability, protecting the spinal cord and nerve roots, and enabling movement of the spine. Pathologies affecting the posterior elements can cause significant pain and disability. Imaging techniques, such as conventional radiography, computed tomography, and magnetic resonance imaging, are crucial for the diagnosis and evaluation of pathology, enabling accurate localization, characterization, and staging of the disease.

The Impact of a Public Health Campaign to Deter Viewing of Child Sexual Abuse Images Online: A Case Study of the UK Stop It Now! Campaign.

Public campaigns offer an opportunity to prevent child sexual abuse by raising awareness and promoting help available to bystanders, victims, and those at risk of perpetrating the abuse. This paper explores the impact of The Lucy Faithfull Foundation's 'Stop It Now!' campaign in the UK (2015-2018) on help-seeking. Helpline calls (11,190 unique callers), website analytics (109,432 new website visitors) and three website-hosted surveys (N = 252) provided data on help-seeking, awareness, and self-reported behavior. Results indicated that there were more visitors to the help website during active campaigning periods, and helpline callers and website visitors were more likely to seek help after viewing campaign materials during active than non-active campaign periods. Help-seekers were predominantly men concerned about their own behavior. Survey 2 respondents concerned about their own behavior (n = 53) indicated that their awareness of the law (75.5%), and legal and personal consequences (67.9%) had changed after hearing about the campaign, and 66% reported a change in behavior. Public health campaigns may be an effective way to promote help-seeking and prevent abuse.

Collecting Marine Gnathiid Isopod Fish Parasites with Light Traps.

A method to collect marine gnathiid isopod fish parasites with the use of light traps is presented. Gnathiid isopods are a major group of marine fish parasites that feed on blood and fluid from host fishes, mostly at night. Like ticks and mosquitos on land, they associate only temporarily with their host and spend most of their life free-living in the benthos. Given their high mobility and transient and predominantly nocturnal association with hosts, they cannot easily be collected by capturing free-living hosts. However, they are readily attracted to underwater light sources, creating the opportunity to collect them in light traps. Here the design and individual steps involved in the deployment and processing of specially adapted light traps for collecting free-living stages of gnathiid isopods are outlined. Sample results and possible modifications of the basic protocol for a variety of different sampling needs are presented and discussed.

Nonlinear Perturbation of Random Matrix Theory.

We consider a system of linear oscillators, or quantum states, described by random matrix theory and analyze how its time evolution is affected by a nonlinear perturbation. Our numerical results show that above a certain chaos border a weak or moderate nonlinearity leads to a dynamical thermalization of a finite number of degrees of freedom with energy equipartition over linear eigenmodes as expected from the laws of classical statistical mechanics. The system temperature is shown to change in a broad range from positive to negative values, and the dependence of system characteristics on the initial injected energy is determined. Below the chaos border the dynamics is described by the Kolmogorov-Arnold-Moser integrability. Owing to universal features of random matrix theory we argue that the obtained results describe the generic properties of its nonlinear perturbation.

Time-resolved cryo-EM (TR-EM) analysis of substrate polyubiquitination by the RING E3 anaphase-promoting complex/cyclosome (APC/C).

Substrate polyubiquitination drives a myriad of cellular processes, including the cell cycle, apoptosis and immune responses. Polyubiquitination is highly dynamic, and obtaining mechanistic insight has thus far required artificially trapped structures to stabilize specific steps along the enzymatic process. So far, how any ubiquitin ligase builds a proteasomal degradation signal, which is canonically regarded as four or more ubiquitins, remains unclear. Here we present time-resolved cryogenic electron microscopy studies of the 1.2 MDa E3 ubiquitin ligase, known as the anaphase-promoting complex/cyclosome (APC/C), and its E2 co-enzymes (UBE2C/UBCH10 and UBE2S) during substrate polyubiquitination. Using cryoDRGN (Deep Reconstructing Generative Networks), a neural network-based approach, we reconstruct the conformational changes undergone by the human APC/C during polyubiquitination, directly visualize an active E3-E2 pair modifying its substrate, and identify unexpected interactions between multiple ubiquitins with parts of the APC/C machinery, including its coactivator CDH1. Together, we demonstrate how modification of substrates with nascent ubiquitin chains helps to potentiate processive substrate polyubiquitination, allowing us to model how a ubiquitin ligase builds a proteasomal degradation signal.

Neutron-activated, plasmonically excitable Fe-Pt-Yb2O3 nanoparticles delivering anti-cancer radiation against human glioblastoma cells.

Magnetic nanoparticles can be functionalized in many ways for biomedical applications. Here, we combine four advantageous features in a novel Fe-Pt-Yb2O3 core-shell nanoparticle. (a) The nanoparticles have a size of 10 nm allowing them to diffuse through neuronal tissue. (b) The particles are superparamagnetic after synthesis and ferromagnetic after annealing, enabling directional control by magnetic fields, enhance NMRI contrast, and hyperthermia treatment. (c) After neutron-activation of the shell, they carry low-energetic, short half-life ß-radiation from 175Yb, 177Yb, and 177Lu. (d) Additionally, the particles can be optically visualized by plasmonic excitation and luminescence. To demonstrate the potential of the particles for cancer treatment, we exposed cultured human glioblastoma cells (LN-18) to non-activated and activated particles to confirm that the particles are internalized, and that the ß-radiation of the radioisotopes incorporated in the neutron-activated shell of the nanoparticles kills more than 98% of the LN-18 cancer cells, promising for future anti-cancer applications.

ICU- and ventilator-free days with isoflurane or propofol as a primary sedative - A post- hoc analysis of a randomized controlled trial.

PURPOSE: To compare ICU-free (ICU-FD) and ventilator-free days (VFD) in the 30 days after randomization in patients that received isoflurane or propofol without receiving the other sedative. MATERIALS AND METHODS: A recent randomized controlled trial (RCT) compared inhaled isoflurane via the Sedaconda® anaesthetic conserving device (ACD) with intravenous propofol for up to 54 h (Meiser et al. 2021). After end of study treatment, continued sedation was locally determined. Patients were eligible for this post-hoc analysis only if they had available 30-day follow-up data and never converted to the other drug in the 30 days from randomization. Data on ventilator use, ICU stay, concomitant sedative use, renal replacement therapy (RRT) and mortality were collected. RESULTS: Sixty-nine of 150 patients randomized to isoflurane and 109 of 151 patients randomized to propofol were eligible. After adjusting for potential confounders, the isoflurane group had more ICU-FD than the propofol group (17.3 vs 13.8 days, p = 0.028). VFD for the isoflurane and propofol groups were 19.8 and 18.5 respectively (p = 0.454). Other sedatives were used more frequently (p < 0.0001) and RRT started in a greater proportion of patients in the propofol group (p = 0.011). CONCLUSIONS: Isoflurane via the ACD was not associated with more VFD but with more ICU-FD and less concomitant sedative use.

Breast Cancer Stem Cell-Derived Tumors Escape from γδ T-cell Immunosurveillance In Vivo by Modulating γδ T-cell Ligands.

There are no targeted therapies for patients with triple-negative breast cancer (TNBC). TNBC is enriched in breast cancer stem cells (BCSC), which play a key role in metastasis, chemoresistance, relapse, and mortality. γδ T cells hold great potential in immunotherapy against cancer and might provide an approach to therapeutically target TNBC. γδ T cells are commonly observed to infiltrate solid tumors and have an extensive repertoire of tumor-sensing mechanisms, recognizing stress-induced molecules and phosphoantigens (pAgs) on transformed cells. Herein, we show that patient-derived triple-negative BCSCs are efficiently recognized and killed by ex vivo expanded γδ T cells from healthy donors. Orthotopically xenografted BCSCs, however, were refractory to γδ T-cell immunotherapy. We unraveled concerted differentiation and immune escape mechanisms: xenografted BCSCs lost stemness, expression of γδ T-cell ligands, adhesion molecules, and pAgs, thereby evading immune recognition by γδ T cells. Indeed, neither promigratory engineered γδ T cells, nor anti-PD-1 checkpoint blockade, significantly prolonged overall survival of tumor-bearing mice. BCSC immune escape was independent of the immune pressure exerted by the γδ T cells and could be pharmacologically reverted by zoledronate or IFNα treatment. These results pave the way for novel combinatorial immunotherapies for TNBC.

Rho MultiBinder, a fluorescent biosensor that reports the activity of multiple GTPases.

Imaging two or more fluorescent biosensors in the same living cell can reveal the spatiotemporal coordination of protein activities. However, using multiple Förster resonance energy transfer (FRET) biosensors together is challenging due to toxicity and the need for orthogonal fluorophores. Here we generate a biosensor component that binds selectively to the activated conformation of three different proteins. This enabled multiplexed FRET with fewer fluorophores, and reduced toxicity. We generated this MultiBinder (MB) reagent for the GTPases RhoA, Rac1, and Cdc42 by combining portions of the downstream effector proteins Pak1 and Rhotekin. Using FRET between mCherry on the MB and YPet or mAmetrine on two target proteins, the activities of any pair of GTPases could be distinguished. The MB was used to image Rac1 and RhoA together with a third, dye-based biosensor for Cdc42. Quantifying effects of biosensor combinations on the frequency, duration, and velocity of cell protrusions and retractions demonstrated reduced toxicity. Multiplexed imaging revealed signaling hierarchies between the three proteins at the cell edge where they regulate motility.