Perivascular macrophages mediate neutrophil recruitment during bacterial skin infection.

Transendothelial migration of neutrophils in postcapillary venules is a key event in the inflammatory response against pathogens and tissue damage. The precise regulation of this process is incompletely understood. We report that perivascular macrophages are critical for neutrophil migration into skin infected with the pathogen Staphylococcus aureus. Using multiphoton intravital microscopy we showed that neutrophils extravasate from inflamed dermal venules in close proximity to perivascular macrophages, which are a major source of neutrophil chemoattractants. The virulence factor α-hemolysin produced by S. aureus lyses perivascular macrophages, which leads to decreased neutrophil transmigration. Our data illustrate a previously unrecognized role for perivascular macrophages in neutrophil recruitment to inflamed skin and indicate that S. aureus uses hemolysin-dependent killing of these cells as an immune evasion strategy.

A Liver Capsular Network of Monocyte-Derived Macrophages Restricts Hepatic Dissemination of Intraperitoneal Bacteria by Neutrophil Recruitment.

The liver is positioned at the interface between two routes traversed by pathogens in disseminating infection. Whereas blood-borne pathogens are efficiently cleared in hepatic sinusoids by Kupffer cells (KCs), it is unknown how the liver prevents dissemination of peritoneal pathogens accessing its outer membrane. We report here that the hepatic capsule harbors a contiguous cellular network of liver-resident macrophages phenotypically distinct from KCs. These liver capsular macrophages (LCMs) were replenished in the steady state from blood monocytes, unlike KCs that are embryonically derived and self-renewing. LCM numbers increased after weaning in a microbiota-dependent process. LCMs sensed peritoneal bacteria and promoted neutrophil recruitment to the capsule, and their specific ablation resulted in decreased neutrophil recruitment and increased intrahepatic bacterial burden. Thus, the liver contains two separate and non-overlapping niches occupied by distinct resident macrophage populations mediating immunosurveillance at these two pathogen entry points to the liver.

Cutaneous immunosurveillance and regulation of inflammation by group 2 innate lymphoid cells.

Type 2 immunity is critical for defense against cutaneous infections but also underlies the development of allergic skin diseases. We report the identification in normal mouse dermis of an abundant, phenotypically unique group 2 innate lymphoid cell (ILC2) subset that depended on interleukin 7 (IL-7) and constitutively produced IL-13. Intravital multiphoton microscopy showed that dermal ILC2 cells specifically interacted with mast cells, whose function was suppressed by IL-13. Treatment of mice deficient in recombination-activating gene 1 (Rag1(-/-)) with IL-2 resulted in the population expansion of activated, IL-5-producing dermal ILC2 cells, which led to spontaneous dermatitis characterized by eosinophil infiltrates and activated mast cells. Our data show that ILC2 cells have both pro- and anti-inflammatory properties and identify a previously unknown interactive pathway between two innate populations of cells of the immune system linked to type 2 immunity and allergic diseases.

An N-nitrosating metalloenzyme constructs the pharmacophore of streptozotocin.

Small molecules containing the N-nitroso group, such as the bacterial natural product streptozotocin, are prominent carcinogens1,2 and important cancer chemotherapeutics3,4. Despite the considerable importance of this functional group to human health, enzymes dedicated to the assembly of the N-nitroso unit have not been identified. Here we show that SznF, a metalloenzyme from the biosynthesis of streptozotocin, catalyses an oxidative rearrangement of the guanidine group of Nω-methyl-L-arginine to generate an N-nitrosourea product. Structural characterization and mutagenesis of SznF reveal two separate active sites that promote distinct steps in this transformation using different iron-containing metallocofactors. This biosynthetic reaction, which has little precedent in enzymology or organic synthesis, expands the catalytic capabilities of non-haem-iron-dependent enzymes to include N-N bond formation. We find that biosynthetic gene clusters that encode SznF homologues are widely distributed among bacteria-including environmental organisms, plant symbionts and human pathogens-which suggests an unexpectedly diverse and uncharacterized microbial reservoir of bioactive N-nitroso metabolites.

The distinctive weathering crust habitat of a High Arctic glacier comprises discrete microbial micro-habitats.

Sunlight penetrates the ice surfaces of glaciers and ice sheets, forming a water-bearing porous ice matrix known as the weathering crust. This crust is home to a significant microbial community. Despite the potential implications of microbial processes in the weathering crust for glacial melting, biogeochemical cycles, and downstream ecosystems, there have been few explorations of its microbial communities. In our study, we used 16S rRNA gene sequencing and shotgun metagenomics of a Svalbard glacier surface catchment to characterise the microbial communities within the weathering crust, their origins and destinies, and the functional potential of the weathering crust metagenome. Our findings reveal that the bacterial community in the weathering crust is distinct from those in upstream and downstream habitats. However, it comprises two separate micro-habitats, each with different taxa and functional categories. The interstitial porewater is dominated by Polaromonas, influenced by the transfer of snowmelt, and exported via meltwater channels. In contrast, the ice matrix is dominated by Hymenobacter, and its metagenome exhibits a diverse range of functional adaptations. Given that the global weathering crust area and the subsequent release of microbes from it are strongly responsive to climate projections for the rest of the century, our results underscore the pressing need to integrate the microbiome of the weathering crust with other communities and processes in glacial ecosystems.

Melanocytes in regenerative medicine applications and disease modeling.

Melanocytes are dendritic cells localized in skin, eyes, hair follicles, ears, heart and central nervous system. They are characterized by the presence of melanosomes enriched in melanin which are responsible for skin, eye and hair pigmentation. They also have different functions in photoprotection, immunity and sound perception. Melanocyte dysfunction can cause pigmentary disorders, hearing and vision impairments or increased cancer susceptibility. This review focuses on the role of melanocytes in homeostasis and disease, before discussing their potential in regenerative medicine applications, such as for disease modeling, drug testing or therapy development using stem cell technologies, tissue engineering and extracellular vesicles.

LP-118 is a novel B-cell lymphoma 2 / extra-large inhibitor that demonstrates efficacy in models of venetoclax-resistant chronic lymphocytic leukemia.

Patients with chronic lymphocytic leukemia (CLL) respond well to initial treatment with the Bcell lymphoma 2 (BCL2) inhibitor venetoclax. Upon relapse, they often retain sensitivity to BCL2 targeting, but durability of response remains a concern. We hypothesize that targeting both BCL2 and B-cell lymphoma-extra large (BCLXL) will be a successful strategy to treat CLL, including for patients who relapse on venetoclax. To test this hypothesis, we conducted a pre-clinical investigation of LP-118, a highly potent inhibitor of BCL2 with moderate BCLXL inhibition to minimize platelet toxicity. This study demonstrated that LP-118 induces efficient BAK activation, cytochrome C release, and apoptosis in both venetoclax naïve and resistant CLL cells. Significantly, LP-118 is effective in cell lines expressing the BCL2 G101V mutation and in cells expressing BCLXL but lacking BCL2 dependence. Using an immunocompetent mouse model, Eµ-TCL1, LP-118 demonstrates low platelet toxicity, which hampered earlier BCLXL inhibitors. Finally, LP-118 in the RS4;11 and OSU-CLL xenograft models results in decreases in tumor burden and survival advantage, respectively. These results provide a mechanistic rationale for the evaluation of LP-118 for the treatment of venetoclax responsive and relapsed CLL.

Many-Body Quantum Interference Route to the Two-Channel Kondo Effect: Inverse Design for Molecular Junctions and Quantum Dot Devices.

Molecular junctions-whether actual single molecules in nanowire break junctions or artificial molecules realized in coupled quantum dot devices-offer unique functionality due to their orbital complexity, strong electron interactions, gate control, and many-body effects from hybridization with the external electronic circuit. Inverse design involves finding candidate structures that perform a desired function optimally. Here we develop an inverse design strategy for generalized quantum impurity models describing molecular junctions, and as an example, use it to demonstrate that many-body quantum interference can be leveraged to realize the two-channel Kondo critical point in simple 4- or 5-site molecular moieties. We show that remarkably high Kondo temperatures can be achieved, meaning that entropy and transport signatures should be experimentally accessible.

Identifying the Number of Steps Required for Familiarisation to Athletic Footwear in Healthy Older Adults.

INTRODUCTION: Research on athletic footwear familiarisation within an older population is sparse. This is problematic because unfamiliar footwear may act as a new perturbation and modify older adults' walking gait and stability. In addition, while athletic footwear has been suggested to enhance older adults' comfort and support during activities of daily living, the necessary period for familiarisation with athletic footwear is unknown. Therefore, this study aimed to identify the number of steps required for older adults to be familiarised with athletic footwear of different midsole thicknesses. METHODS: Twenty-six healthy and physically active community-dwelling older adults, 21 females (71.1 ± 4.5 years; 164.5 ± 5.3 cm; 68.4 ± 11.4 kg) and five males (70.6 ± 2.3 years; 175.2 ± 7.8 cm; 72.8 ± 9.7 kg), completed a walking-based protocol. Participants walked two trials of 200 steps at their habitual speed on a 10-m track of an optical measurement system in three footwear conditions: (1) New Balance® REVlite 890v6 (thick midsole); (2) New Balance® REVlite 1400v5 (moderate midsole); and (3) New Balance® Minimus 20v7 (thin midsole). Gait speed (m.s-1) and walking time (min) were analysed for each participant over the 400 steps. Number of required familiarisation steps were established over three analysis phases, consisting of steady-state gait assessment, averaging and analysis of blocks of 40 steps, and sequentially comparing these steps with a predetermined threshold. Footwear familiarisation was assumed when the mean gait speed fell within an acceptable level (±2 SD from 320 to 360 step values) and subsequently maintained. RESULTS: Most participants were familiarised with all three footwear conditions (thick n = 18; moderate and thin n = 20) after walking 80 steps. For all participants, the moderate midsole had the shortest familiarisation period (160 steps). The highest number of familiarisation steps was found in the thick (320 steps) and thin midsoles (240 steps) for some participants. CONCLUSION: A minimum of 320 familiarisation steps is recommended to account for both individual differences and midsole thicknesses. Implementing this walking-based footwear familiarisation protocol would improve validity of future studies, ensuring they analyse footwear effects rather than familiarisation with the footwear.

Decoding allosteric regulation by the acyl carrier protein.

Enzymes in multistep metabolic pathways utilize an array of regulatory mechanisms to maintain a delicate homeostasis [K. Magnuson, S. Jackowski, C. O. Rock, J. E. Cronan, Jr, Microbiol. Rev. 57, 522-542 (1993)]. Carrier proteins in particular play an essential role in shuttling substrates between appropriate enzymes in metabolic pathways. Although hypothesized [E. Ploskon et al., Chem. Biol. 17, 776-785 (2010)], allosteric regulation of substrate delivery has never before been demonstrated for any acyl carrier protein (ACP)-dependent pathway. Studying these mechanisms has remained challenging due to the transient and dynamic nature of protein-protein interactions, the vast diversity of substrates, and substrate instability [K. Finzel, D. J. Lee, M. D. Burkart, ChemBioChem 16, 528-547 (2015)]. Here we demonstrate a unique communication mechanism between the ACP and partner enzymes using solution NMR spectroscopy and molecular dynamics to elucidate allostery that is dependent on fatty acid chain length. We demonstrate that partner enzymes can allosterically distinguish between chain lengths via protein-protein interactions as structural features of substrate sequestration are translated from within the ACP four-helical bundle to the protein surface, without the need for stochastic chain flipping. These results illuminate details of cargo communication by the ACP that can serve as a foundation for engineering carrier protein-dependent pathways for specific, desired products.

Worldwide revision of synanthropic silverfish (Insecta: Zygentoma: Lepismatidae) combining morphological and molecular data.

Synanthropic silverfish are the best-known and most widely distributed insects of the order Zygentoma. However, there is a great gap in the knowledge and confusion about the geographic distribution and the diagnostic characteristics that allow their identification. In this work, we provide an exhaustive and deep analysis of the most common 9 synanthropic silverfish of the world, combining previously published and newly derived morphological and molecular data. Updated descriptions of Ctenolepisma calvum (Ritter, 1910) and Ctenolepisma (Sceletolepisma) villosum (Fabricius, 1775) are included, and morphological remarks, illustrations, and photographs of the remaining synanthropic species are provided to clarify their diagnosis and differentiation among them and from other free-living species. In addition, Ctenolepisma targionii (Grassi and Rovelli, 1889) is synonymized with C. villosum. A molecular phylogeny is presented based on the COI sequences of all the synanthropic species deposited in BOLD and GenBank, with 15 new sequences provided by this study. This has allowed us to detect and correct a series of identification errors based on the lack of morphological knowledge of several species. Moreover, 2 different lineages of Ctenolepisma longicaudatumEscherich, 1905 have also been detected. To help future studies, we also provide a taxonomic interpretation guide for the most important diagnostic characters of the order Zygentoma, as well as an identification key for all the Synanthropic studied species. Finally, an approximation of the global distribution of synanthropic silverfish is discussed. Several new records indicate that the expansion of these species, generally associated with the transport of goods and people, is still far from over.

Multifractal Analysis of Measures Arising from Random Substitutions.

We study regularity properties of frequency measures arising from random substitutions, which are a generalisation of (deterministic) substitutions where the substituted image of each letter is chosen independently from a fixed finite set. In particular, for a natural class of such measures, we derive a closed-form analytic formula for the Lq-spectrum and prove that the multifractal formalism holds. This provides an interesting new class of measures satisfying the multifractal formalism. More generally, we establish results concerning the Lq-spectrum of a broad class of frequency measures. We introduce a new notion called the inflation word Lq-spectrum of a random substitution and show that this coincides with the Lq-spectrum of the corresponding frequency measure for all q≥0. As an application, we obtain closed-form formulas under separation conditions and recover known results for topological and measure theoretic entropy.

Pain-free bite force in a healthy population: Within-session test-retest reliability in different sitting positions.

BACKGROUND: Pain-free bite force (PFBF) is a promising measure to evaluate bite function in temporomandibular disorders (TMDs), yet the reliability of the measure is unknown. OBJECTIVES: Establish the (1) within-session test-retest reliability of PFBF in a healthy population for a single and mean of three trials in supported and unsupported sitting; (2) standard error of measurement (SEM) and minimal detectable change (MDC). METHODS: Thirty healthy participants (n = 15 female, mean [SD] age = 34.4 [11.0] years) completed two sessions (30-60 min apart) comprising three PFBF trials on each side, in both supported and unsupported sitting, to provide data for 60 (30 participants × two sides) test-retest assessments. Test-retest reliability for the first trial and mean of three trials in each position were determined using intraclass correlation coefficients (ICCs), before calculating the corresponding SEM and MDC for males (M) and females (F) respectively. RESULTS: Within-session reliability was considered excellent for a single trial in supported sitting (ICC = 0.85; SEM M/F = 99/84 N; MDC M/F = 275/232 N) and unsupported sitting (ICC = 0.91; SEM M/F = 72/59 N, MDC M/F = 200/163 N), and for a mean of three trials in supported sitting (ICC = 0.89; SEM M/F = 66/79 N, MDC M/F = 182/220 N) and unsupported sitting (ICC = 0.92; SEM M/F = 64/59 N, MDC M/F = 177/164 N). CONCLUSION: Single and a mean of three trials in supported and unsupported sitting appear reliable methods to measure PFBF in a healthy population. Testing PFBF using a mean of three trials in unsupported sitting appears superior over other methods though due to higher test-retest reliability, and lower SEM and MDC. Future studies should examine the reliability of PFBF in TMD populations.

The management of a professional footballer recovering from a surgical repair of the proximal adductor longus tendon through a return-to-performance pathway. A case report.

This case report details the management of a 23-year-old professional footballer who sustained a rupture of the proximal adductor longus (AL) tendon. Following surgical reattachment of the tendon, the player completed an eleven-phase return to performance (RTPerf) pathway designed to ensure a rapid and safe return to play (RTPlay). The pathway uses distinct phases that incorporate clinical, performance, and sport-specific criteria to guide decision-making throughout the process. This case report outlines the phases and criteria used in conjunction with shared decision-making by the interdisciplinary team (IDT) to ensure a successful RTPlay. The effectiveness of this pathway was demonstrated by the player's return to competitive play 12 weeks post-surgery.

Inferring Mycobacterium bovis transmission between cattle and badgers using isolates from the Randomised Badger Culling Trial.

Mycobacterium bovis (M. bovis) is a causative agent of bovine tuberculosis, a significant source of morbidity and mortality in the global cattle industry. The Randomised Badger Culling Trial was a field experiment carried out between 1998 and 2005 in the South West of England. As part of this trial, M. bovis isolates were collected from contemporaneous and overlapping populations of badgers and cattle within ten defined trial areas. We combined whole genome sequences from 1,442 isolates with location and cattle movement data, identifying transmission clusters and inferred rates and routes of transmission of M. bovis. Most trial areas contained a single transmission cluster that had been established shortly before sampling, often contemporaneous with the expansion of bovine tuberculosis in the 1980s. The estimated rate of transmission from badger to cattle was approximately two times higher than from cattle to badger, and the rate of within-species transmission considerably exceeded these for both species. We identified long distance transmission events linked to cattle movement, recurrence of herd breakdown by infection within the same transmission clusters and superspreader events driven by cattle but not badgers. Overall, our data suggests that the transmission clusters in different parts of South West England that are still evident today were established by long-distance seeding events involving cattle movement, not by recrudescence from a long-established wildlife reservoir. Clusters are maintained primarily by within-species transmission, with less frequent spill-over both from badger to cattle and cattle to badger.

Z_{3} Parafermion in the Double Charge Kondo Model.

Quantum impurity models with frustrated Kondo interactions can support quantum critical points with fractionalized excitations. Recent experiments [W. Pouse et al., Nat. Phys. (2023)NPAHAX1745-247310.1038/s41567-022-01905-4] on a circuit containing two coupled metal-semiconductor islands exhibit transport signatures of such a critical point. Here, we show using bosonization that the double charge-Kondo model describing the device can be mapped in the Toulouse limit to a sine-Gordon model. Its Bethe-ansatz solution shows that a Z_{3} parafermion emerges at the critical point, characterized by a fractional 1/2ln(3) residual entropy, and scattering fractional charges e/3. We also present full numerical renormalization group calculations for the model and show that the predicted behavior of conductance is consistent with experimental results.

Electrocardiogram-based biometrics for user identification - Using your heartbeat as a digital key.

External biometrics such as thumbprint and facial recognition have become standard tools for securing our digital devices and protecting our data. These systems, however, are potentially prone to copying and cybercrime access. Researchers have therefore explored internal biometrics, such as the electrical patterns within an electrocardiogram (ECG). The heart's electrical signals carry sufficient distinctiveness to allow the ECG to be used as an internal biometric for user authentication and identification. Using the ECG in this way has many potential advantages and limitations. This article reviews the history of ECG biometrics and explores some of the technical and security considerations. It also explores current and future uses of the ECG as an internal biometric.

Soundscape experience of public spaces in different world regions: A comparison between the European and Chinese contexts via a large-scale on-site surveya).

The influence of cultural background on the soundscape experience in public spaces has been widely acknowledged. However, most studies have not used standardized protocols for soundscape perception data collection, nor have they gathered large datasets across different regions of the world to investigate possible cultural differences. This study explored the relationships between soundscape descriptors, perceived dominance of sound sources, and overall soundscape qualities and whether these relationships differ across world regions. A database of over 2000 soundscape surveys was collected in situ in outdoor public spaces in Europe and China. Results highlighted differences in how European and Chinese participants perceived the pleasantness and dominance of different sound sources. Specifically, the positive correlation between perceived pleasantness and natural sounds was stronger for European participants. For Chinese participants, vibrant soundscapes were positively correlated with perceived dominance of natural sounds, whereas in Europe, they were associated more with human-generated sounds. Perceived loudness had a greater effect on the appropriateness dimension for the Chinese sample than that for the European sample. This study provides a deeper understanding of how the geographical/cultural context can influence soundscape perception in public spaces and suggests that such country-specific factors should be considered when designing urban soundscapes.

AI-based soundscape analysis: Jointly identifying sound sources and predicting annoyancea).

Soundscape studies typically attempt to capture the perception and understanding of sonic environments by surveying users. However, for long-term monitoring or assessing interventions, sound-signal-based approaches are required. To this end, most previous research focused on psycho-acoustic quantities or automatic sound recognition. Few attempts were made to include appraisal (e.g., in circumplex frameworks). This paper proposes an artificial intelligence (AI)-based dual-branch convolutional neural network with cross-attention-based fusion (DCNN-CaF) to analyze automatic soundscape characterization, including sound recognition and appraisal. Using the DeLTA dataset containing human-annotated sound source labels and perceived annoyance, the DCNN-CaF is proposed to perform sound source classification (SSC) and human-perceived annoyance rating prediction (ARP). Experimental findings indicate that (1) the proposed DCNN-CaF using loudness and Mel features outperforms the DCNN-CaF using only one of them. (2) The proposed DCNN-CaF with cross-attention fusion outperforms other typical AI-based models and soundscape-related traditional machine learning methods on the SSC and ARP tasks. (3) Correlation analysis reveals that the relationship between sound sources and annoyance is similar for humans and the proposed AI-based DCNN-CaF model. (4) Generalization tests show that the proposed model's ARP in the presence of model-unknown sound sources is consistent with expert expectations and can explain previous findings from the literature on soundscape augmentation.

Participant-Level Analysis of the Effects of Interventions on Patient-Reported Outcomes in Patients With Chronic Ankle Instability.

CONTEXT: Intervention studies for chronic ankle instability (CAI) often focus on improving physical impairments of the ankle complex. However, using an impairments-focused approach may miss psychological factors that may mediate function and recovery. Patient-reported outcome (PRO) measures can be used to assess several dimensions of the health-related quality of life (HRQoL) and deliver enhanced patient-centered care. Therefore, the purpose of this investigation was to evaluate group-level improvements in HRQoL and treatment response rates following various interventions in patients with CAI. DESIGN: Cross-sectional. METHODS: Data from 7 previous studies were pooled by the chronic ankle instability outcomes network for participant-level analysis, resulting in 136 patients with CAI. Several interventions were assessed including balance training, gait biofeedback, joint mobilizations, stretching, and strengthening, with treatment volume ranging from 1 to 4 weeks. Outcome measures were PROs that assessed ankle-specific function (Foot and Ankle Ability Measure), injury-related fear (Tampa Scale of Kinesiophobia and Fear Avoidance Belief Questionnaire), and global well-being (Disablement in the Physically Active); the PROs assessed varied between studies. Preintervention to postintervention changes were evaluated using separate Wilcoxon signed-rank tests and effect sizes, and a responder analysis was conducted for each PRO. RESULTS: Significant, moderate to large improvements were observed in PROs that assessed ankle-specific function, injury-related fear, and global well-being following intervention (P < .001). Responder rates ranged from 39.0% to 53.3%, 12.8% to 51.4%, and 37.8% for ankle specific function, injury-related fear, and global well-being, respectively. CONCLUSIONS: Various interventions can lead to positive improvements in HRQoL in patients with CAI. Treatment response rates at improving HRQoL are similar to response rates at improving impairments such as balance, further reinforcing the need for individualized treatment approaches when treating a patient with CAI.