Translocation of Viable Gut Microbiota to Mesenteric Adipose Drives Formation of Creeping Fat in Humans.

A mysterious feature of Crohn's disease (CD) is the extra-intestinal manifestation of "creeping fat" (CrF), defined as expansion of mesenteric adipose tissue around the inflamed and fibrotic intestine. In the current study, we explore whether microbial translocation in CD serves as a central cue for CrF development. We discovered a subset of mucosal-associated gut bacteria that consistently translocated and remained viable in CrF in CD ileal surgical resections, and identified Clostridium innocuum as a signature of this consortium with strain variation between mucosal and adipose isolates, suggesting preference for lipid-rich environments. Single-cell RNA sequencing characterized CrF as both pro-fibrotic and pro-adipogenic with a rich milieu of activated immune cells responding to microbial stimuli, which we confirm in gnotobiotic mice colonized with C. innocuum. Ex vivo validation of expression patterns suggests C. innocuum stimulates tissue remodeling via M2 macrophages, leading to an adipose tissue barrier that serves to prevent systemic dissemination of bacteria.

The Contribution of the Distal Oblique Band to Distal Radioulnar Joint Stability.

PURPOSE: The distal radioulnar joint (DRUJ) is supported by an array of dynamic and static stabilizers, of which the triangular fibrocartilage complex (TFCC) is the most important, and the distal interosseous ligament is next in importance. The distal oblique band (DOB) is an identifiable component of the distal interosseous ligament, found in a subset of the population. Our objective was to determine the contribution of the DOB to DRUJ stability in the presence of a disrupted TFCC. METHODS: Twenty-three above-elbow specimens were prepared by removing the TFCC and the DRUJ joint capsule, preserving the distal interosseous ligament and the pronator quadratus. Cadavers were stratified into two groups-those with, and those without a DOB. A bone plate and screws were attached to the ulna; then, a transverse load was applied to failure, creating a diastasis between the radius and ulna. RESULTS: The group with a DOB had a mean load at failure of 160.7 ± 46.5 N. The group without a DOB had a mean load at failure of 148.0 ± 26.3 N. Stiffness prior to failure was 16.9 N/mm in the group with a DOB and 12.4 N/mm in the group without a DOB. CONCLUSIONS: The current results indicate that the DOB may not substantially contribute to DRUJ stability in the presence of a disrupted TFCC. CLINICAL RELEVANCE: Stability of the DRUJ after TFCC injury may not be substantially improved by the presence of a DOB. Thus, the clinical importance of DOB reconstruction remains unclear.

Covalent-reversible peptide-based protease inhibitors. Design, synthesis, and clinical success stories.

Dysregulated human peptidases are implicated in a large variety of diseases such as cancer, hypertension, and neurodegeneration. Viral proteases for their part are crucial for the pathogens' maturation and assembly. Several decades of research were devoted to exploring these precious therapeutic targets, often addressing them with synthetic substrate-based inhibitors to elucidate their biological roles and develop medications. The rational design of peptide-based inhibitors offered a rapid pathway to obtain a variety of research tools and drug candidates. Non-covalent modifiers were historically the first choice for protease inhibition due to their reversible enzyme binding mode and thus presumably safer profile. However, in recent years, covalent-irreversible inhibitors are having a resurgence with dramatic increase of their related publications, preclinical and clinical trials, and FDA-approved drugs. Depending on the context, covalent modifiers could provide more effective and selective drug candidates, hence requiring lower doses, thereby limiting off-target effects. Additionally, such molecules seem more suitable to tackle the crucial issue of cancer and viral drug resistances. At the frontier of reversible and irreversible based inhibitors, a new drug class, the covalent-reversible peptide-based inhibitors, has emerged with the FDA approval of Bortezomib in 2003, shortly followed by 4 other listings to date. The highlight in the field is the breathtakingly fast development of the first oral COVID-19 medication, Nirmatrelvir. Covalent-reversible inhibitors can hipothetically provide the safety of the reversible modifiers combined with the high potency and specificity of their irreversible counterparts. Herein, we will present the main groups of covalent-reversible peptide-based inhibitors, focusing on their design, synthesis, and successful drug development programs.

Potentially Inappropriate Medications are Associated With Geriatric Trauma Recidivism.

INTRODUCTION: The American Geriatric Society has identified polypharmacy and categories of potentially inappropriate medication (PIM) that should be avoided in the elderly. These medications can potentially cause an increased risk of falls and traumatic events. MATERIALS AND METHODS: We conducted a retrospective study on elderly patients with traumatic injuries at a Level 1 trauma center. We compared patients having only one traumatic event and those with one or more traumatic events with the presence of prescriptions for PIMs. RESULTS: Identified high risk categories of anticoagulant and antiplatelet agents (odds ratio [OR] 1.18, 95% confidence interval [CI] 1.08-1.28), psychiatric and neurologic agents (OR 1.32, 95% CI 1.22-1.43), as well as medication with anticholinergic properties (OR 1.14, 95% CI 1.03-1.27) were associated with an increased risk of recurrent trauma. CONCLUSIONS: We can quantify the risk of recurrent trauma with certain categories of PIM. Medication reconciliation and shared decision-making regarding the continued use of these medications may positively impact trauma recidivism.

Diversity of mitochondrial DNA in 3 species of great whales before and after modern whaling.

The 20th century commercial whaling industry severely reduced populations of great whales throughout the Southern Hemisphere. The effect of this exploitation on genetic diversity and population structure remains largely undescribed. Here, we compare pre- and post-whaling diversity of mitochondrial DNA (mtDNA) control region sequences for 3 great whales in the South Atlantic, such as the blue, humpback, and fin whale. Pre-whaling diversity is described from mtDNA extracted from bones collected near abandoned whaling stations, primarily from the South Atlantic island of South Georgia. These bones are known to represent the first stage of 20th century whaling and thus pre-whaling diversity of these populations. Post-whaling diversity is described from previously published studies reporting large-scale sampling of living whales in the Southern Hemisphere. Despite relatively high levels of surviving genetic diversity in the post-whaling populations, we found evidence of a probable loss of mtDNA lineages in all 3 species. This is evidenced by the detection of a large number of haplotypes found in the pre-whaling samples that are not present in the post-whaling samples. A rarefaction analysis further supports a loss of haplotypes in the South Atlantic humpback and Antarctic blue whale populations. The bones from former whaling stations in the South Atlantic represent a remarkable molecular archive for further investigation of the decline and ongoing recovery in the great whales of the Southern Hemisphere.

The Unexpected Helical Supramolecular Assembly of a Simple Achiral Acetamide Tecton Generates Selective Water Channels.

Invited for the cover of this issue is the collaborative research team coordinated by Arie van der Lee at the University of Montpellier. The image depicts chiral channels with highly mobile water molecules resulting from the robust self-organization of a simple achiral acetamide. Fully reversible release and re-uptake of water molecules takes place near ambient conditions, with efficient water transport and a good selectivity against NaCl suggesting it to be an efficient candidate for desalination processes. Read the full text of the article at 10.1002/chem.20200383.

The Unexpected Helical Supramolecular Assembly of a Simple Achiral Acetamide Tecton Generates Selective Water Channels.

Achiral 2-hydroxy-N-(diphenylmethyl)acetamide (HNDPA) crystallizes in the P61 chiral space group as a hydrate, building up permeable chiral crystalline helical water channels. The crystallization-driven chiral self-resolution process is highly robust, with the same air-stable crystalline form readily obtained under a variety of conditions. Interestingly, the HNDPA supramolecular helix inner pore is filled by a helical water wire. The whole edifice is mainly stabilized by robust hydrogen bonds involving the HNDPA amide bonds and CH… π interactions between the HNDPA phenyl groups. The crystalline structure shows breathing behavior, with completely reversible release and re-uptake of water inside the chiral channel under ambient conditions. Importantly, the HNDPA channel is able to transport water very efficiently and selectively under biomimetic conditions. With a permeability per channel of 3.3 million water molecules per second in large unilamellar vesicles (LUV) and total selectivity against NaCl, the HNDPA channel is a very promising functional nanomaterial for future applications.

Spectral noise in frequency conversion from the visible to the telecommunication C-band.

We report a detailed study of the noise properties of a visible-to-telecom photon frequency converter based on difference frequency generation (DFG). The device converts 580 nm photons to 1541 nm using a strong pump laser at 930 nm, in a periodically poled lithium niobate ridge waveguide. The converter reaches a maximum device efficiency of 46 % (internal efficiency of 67%) at a pump power of 250 mW. The noise produced by the pump laser is investigated in detail by recording the noise spectra both in the telecom and visible regimes and measuring the power dependence of the noise rates. The noise spectrum in the telecom is very broadband, as expected from previous work on similar DFG converters. However, we also observe several narrow dips in the telecom spectrum, with corresponding peaks appearing in the 580 nm noise spectrum. These features are explained by sum frequency generation of the telecom noise at wavelengths given by the phase-matching condition of different spatial modes in the waveguide. The proposed noise model is in good agreement with all the measured data, including the power dependence of the noise rates, both in the visible and telecom regimes. These results are applicable to the class of DFG converters where the pump laser wavelength is in between the input and target wavelength.

High-rate photon pairs and sequential Time-Bin entanglement with Si3N4 microring resonators.

Integrated photonics is increasing in importance for compact, robust, and scalable enabling quantum technologies. This is particularly interesting for developing quantum communication networks, where resources need to be deployed in the field. We exploit photonic chip-based Si3N4 microring resonators to realise a photon pair source with low-loss, high-noise suppression and coincidence rates of 80×103 s-1. A simple photonic noise characterisation technique is presented that distinguishes linear and nonlinear contributions useful for system design and optimisation. We then demonstrate an all-fiber 750 MHz clock-rate sequential Time-Bin entanglement scheme with raw interference visibilities > 98 %.

Quantum optical frequency up-conversion for polarisation entangled qubits: towards interconnected quantum information devices.

Realising a global quantum network requires combining individual strengths of different quantum systems to perform universal tasks, notably using flying and stationary qubits. However, transferring coherently quantum information between different systems is challenging as they usually feature different properties, notably in terms of operation wavelength and wavepacket. To circumvent this problem for quantum photonics systems, we demonstrate a polarisation-preserving quantum frequency conversion device in which telecom wavelength photons are converted to the near infrared, at which a variety of quantum memories operate. Our device is essentially free of noise, which we demonstrate through near perfect single photon state transfer tomography and observation of high-fidelity entanglement after conversion. In addition, our guided-wave setup is robust, compact, and easily adaptable to other wavelengths. This approach therefore represents a major building block towards advantageously connecting quantum information systems based on light and matter.

The Saline Load Test is Effective at Diagnosing Traumatic Arthrotomies of the Shoulder.

The purpose of this study is to evaluate the fluid volume required for a saline load test to detect intra-articular involvement of the glenohumeral joint after penetrating trauma. A human cadaver study was conducted with 22 thawed, fresh-frozen forequarter amputations. A standard posterior shoulder portal was made with an 11-blade scalpel. A 19-gauge needle was inserted into the anterior portal site, and intra-articular position of both the blade and needle was confirmed with fluoroscopy. The blade was removed and normal saline was injected through the needle until extravasation of fluid was observed through the posterior portal. Injection volume required for extravasation was recorded. A logarithmic distribution of the volumes was then calculated in order to obtain estimated sensitivity ranges. Using a logarithmic distribution, 90%, 95% and 99% of simulated glenohumeral arthrotomies could be detected using injections of: 62 ml [41-96], 81 ml [50-133] and 136 ml [72-252], respectively. (Journal of Surgical Orthopaedic Advances 28(4):268-271, 2019).

Secure Quantum Key Distribution over 421 km of Optical Fiber.

We present a quantum key distribution system with a 2.5 GHz repetition rate using a three-state time-bin protocol combined with a one-decoy approach. Taking advantage of superconducting single-photon detectors optimized for quantum key distribution and ultralow-loss fiber, we can distribute secret keys at a maximum distance of 421 km and obtain secret key rates of 6.5 bps over 405 km.

Development of highly sensitive fluorescent probes for the detection of ß-galactosidase activity - application to the real-time monitoring of senescence in live cells.

We report the development of four novel fluorescent probes to monitor the activity of the ß-galactosidase enzyme (ß-gal), in vitro and in living cells. The fluorophores are based on a 6-amino-styryl-benzothiazole push-pull core and display a strong ICT emission. The probes encompass the fluorescent motif that is connected to a ß-d-galactopyranoside moiety through a self-immolative benzyl carbamate linker (ßGal-1-4). The screening of four different fluorophores enabled us to access new light-up and two-band ratiometric reporters. The four probes, ßGal-1-4, exhibited an extremely fast response and over 200-fold fluorescence enhancement (ßGal-1) following the enzymatic cleavage of the ß-d-galactopyranoside unit. This rapid and extremely sensitive response allowed the detection of senescence-associated ß-galactosidase (SA-ß-gal) activity; a widely used biomarker of senescence. More importantly, ßGal-1 also enabled us to monitor, in real-time, the emergence of senescence in live cells, i.e. the phenotypic transformation from normal to senescent cell. These findings underpin the fact that ßGal-1 may find useful applications in biomedical research. Importantly, ßGal-1 is suitable for epifluorescence and confocal microscopies, and flow cytometry techniques, which are among the most common analytical tools in biology.

Metastatic Melanoma: Insights Into the Evolution of the Treatments and Future Challenges.

Melanoma is the deadliest form of skin cancer. While associated survival prognosis is good when diagnosed early, it dramatically drops when melanoma progresses into its metastatic form. Prior to 2011, the favored therapies include interleukin-2 and chemotherapies, regardless of their low efficiency and their toxicity. Following key biological findings, two new types of therapy have been approved. First, there are the targeted therapies, which rely on small molecule B-Raf and MEK inhibitors and allow the treatment of patients with B-Raf mutated melanoma. Second, there are the immunotherapies, with anti-CTLA-4 and anti-PD-1 antibodies that are used for patients harboring a B-Raf wild-type status. Both approaches have significantly improved patient survival, compared with alkylating agents, in the treatment of unresectable melanoma. Herein, we review the evolution of the treatment of melanoma starting from early discoveries to current therapies. A focus will be provided on drug discovery, synthesis, and mode of action of relevant drugs and the future directions of the domain to overcome the emergence of the resistance events.

Estrogens and androgens inhibit association of RANKL with the pre-osteoblast membrane through post-translational mechanisms.

We have recently demonstrated that RUNX2 promoted, and 17ß-Estradiol (E2) diminished, association of RANKL with the cell membrane in pre-osteoblast cultures. Here we show that, similar to E2, dihydrotestosterone (DHT) diminishes association of RANKL, and transiently transfected GFP-RANKL with the pre-osteoblast membrane without decreasing total RANKL mRNA or protein levels. Diminution of membrane-associated RANKL was accompanied with marked suppression of osteoclast differentiation from co-cultured pre-osteoclasts, even though DHT increased, not decreased, RANKL concentrations in pre-osteoblast conditioned media. A marked decrease in membrane-associated RANKL was observed after 30 min of either E2 or DHT treatment, and near-complete inhibition was observed by 1 hr, suggesting that the diminution of RANKL membrane association was mediated through non-genomic mechanisms. Further indicating dispensability of nuclear action of estrogen receptor, E2-mediated inhibition of RANKL membrane association was mimicked by an estrogen dendrimer conjugate (EDC) that cannot enter the cell nucleus. Finally, the inhibitory effect of E2 and DHT on RANKL membrane association was counteracted by the MMP inhibitor NNGH, and the effect of E2 (and not DHT) was antagonized by the Src inhibitor SU6656. Taken together, these results suggest that estrogens and androgens inhibit osteoblast-driven osteoclastogenesis through non-genomic mechanism(s) that entail, MMP-mediated RANKL dissociation from the cell membrane.

Quantifying Photonic High-Dimensional Entanglement.

High-dimensional entanglement offers promising perspectives in quantum information science. In practice, however, the main challenge is to devise efficient methods to characterize high-dimensional entanglement, based on the available experimental data which is usually rather limited. Here we report the characterization and certification of high-dimensional entanglement in photon pairs, encoded in temporal modes. Building upon recently developed theoretical methods, we certify an entanglement of formation of 2.09(7) ebits in a time-bin implementation, and 4.1(1) ebits in an energy-time implementation. These results are based on very limited sets of local measurements, which illustrates the practical relevance of these methods.

Assessment of new triplet forming artificial nucleobases as RNA ligands directed towards HCV IRES IIId loop.

We report the synthesis of two new artificial nucleobase scaffolds, 1 and 2, featuring adequate hydrogen bonding donors and acceptors for the molecular recognition of U:A and C:G base pairs, respectively. The tethering of these structures to various amino acids and the assessment of these artificial nucleobase-amino acid conjugates as RNA ligands against a model of HCV IRES IIId domain are also reported. Compound 1e displayed the highest affinity (Kd twice lower than neomycin - control). Moreover, it appears that this interaction is enthalpically and entropically favored.

Heralded amplification of photonic qubits.

We demonstrate postselection free heralded qubit amplification for Time-Bin qubits and single photon states in an all-fibre, telecom-wavelength, scheme that highlights the simplicity, stability and potential for fully integrated photonic solutions. Exploiting high-efficiency superconducting detectors, the gain, fidelity and the performance of the amplifier are studied as a function of loss. We also demonstrate the first heralded single photon amplifier with independent sources. This provides a significant advance towards demonstrating device-independent quantum key distribution as well as fundamental tests of quantum mechanics over extended distances.

Quantum Nonlocality with Arbitrary Limited Detection Efficiency.

The demonstration and use of nonlocality, as defined by Bell's theorem, rely strongly on dealing with nondetection events due to losses and detectors'inefficiencies. Otherwise, the so-called detection loophole could be exploited. The only way to avoid this is to have detection efficiencies that are above a certain threshold. We introduce the intermediate assumption of limited detection efficiency, that is, in each run of the experiment, the overall detection efficiency is lower bounded by η(min)>0. Hence, in an adversarial scenario, the adversaries have arbitrary large but not full control over the inefficiencies. We analyze the set of possible correlations that satisfy limited detection locality and show that they necessarily satisfy some linear Bell-like inequalities. We prove that quantum theory predicts the violation of one of these inequalities for all η(min)>0. Hence, nonlocality can be demonstrated with arbitrarily small limited detection efficiencies. We validate this assumption experimentally via a twin-photon implementation in which two users are provided with one photon each out of a partially entangled pair. We exploit on each side a passive switch followed by two measurement devices with fixed settings. Assuming the switches are not fully controlled by an adversary, nor by hypothetical local variables, we reveal the nonlocality of the established correlations despite a low overall detection efficiency.

24-Hour Relativistic Bit Commitment.

Bit commitment is a fundamental cryptographic primitive in which a party wishes to commit a secret bit to another party. Perfect security between mistrustful parties is unfortunately impossible to achieve through the asynchronous exchange of classical and quantum messages. Perfect security can nonetheless be achieved if each party splits into two agents exchanging classical information at times and locations satisfying strict relativistic constraints. A relativistic multiround protocol to achieve this was previously proposed and used to implement a 2-millisecond commitment time. Much longer durations were initially thought to be insecure, but recent theoretical progress showed that this is not so. In this Letter, we report on the implementation of a 24-hour bit commitment solely based on timed high-speed optical communication and fast data processing, with all agents located within the city of Geneva. This duration is more than 6 orders of magnitude longer than before, and we argue that it could be extended to one year and allow much more flexibility on the locations of the agents. Our implementation offers a practical and viable solution for use in applications such as digital signatures, secure voting and honesty-preserving auctions.