Controlling many-body states by the electric-field effect in a two-dimensional material.

To understand the complex physics of a system with strong electron-electron interactions, the ideal is to control and monitor its properties while tuning an external electric field applied to the system (the electric-field effect). Indeed, complete electric-field control of many-body states in strongly correlated electron systems is fundamental to the next generation of condensed matter research and devices. However, the material must be thin enough to avoid shielding of the electric field in the bulk material. Two-dimensional materials do not experience electrical screening, and their charge-carrier density can be controlled by gating. Octahedral titanium diselenide (1T-TiSe2) is a prototypical two-dimensional material that reveals a charge-density wave (CDW) and superconductivity in its phase diagram, presenting several similarities with other layered systems such as copper oxides, iron pnictides, and crystals of rare-earth elements and actinide atoms. By studying 1T-TiSe2 single crystals with thicknesses of 10 nanometres or less, encapsulated in two-dimensional layers of hexagonal boron nitride, we achieve unprecedented control over the CDW transition temperature (tuned from 170 kelvin to 40 kelvin), and over the superconductivity transition temperature (tuned from a quantum critical point at 0 kelvin up to 3 kelvin). Electrically driving TiSe2 over different ordered electronic phases allows us to study the details of the phase transitions between many-body states. Observations of periodic oscillations of magnetoresistance induced by the Little-Parks effect show that the appearance of superconductivity is directly correlated with the spatial texturing of the amplitude and phase of the superconductivity order parameter, corresponding to a two-dimensional matrix of superconductivity. We infer that this superconductivity matrix is supported by a matrix of incommensurate CDW states embedded in the commensurate CDW states. Our results show that spatially modulated electronic states are fundamental to the appearance of two-dimensional superconductivity.

Quantum Dot Parity Effects in Trivial and Topological Josephson Junctions.

An odd-occupied quantum dot in a Josephson junction can flip transmission phase, creating a π junction. When the junction couples topological superconductors, no phase flip is expected. We investigate this and related effects in a full-shell hybrid interferometer, using gate voltage to control dot-junction parity and axial magnetic flux to control the transition from trivial to topological superconductivity. Enhanced zero-bias conductance and critical current for odd parity in the topological phase reflects hybridization of the confined spin with zero-energy modes in the leads.

Cell-surface markers identify tissue resident multipotential stem/stromal cell subsets in synovial intimal and sub-intimal compartments with distinct chondrogenic properties.

OBJECTIVE: Synovium contains multipotent progenitor/stromal cells (MPCs) with potential to participate in cartilage repair. Understanding the identity of these MPCs will allow their therapeutic potential to be fully exploited. Hence this study aimed to identify primary synovial MPCs and characterize them in the context of cartilage regeneration. METHODS: Primary MPC/MPC-subset specific markers in synovium were identified by FACS analysis of uncultured cells. MPC-subsets from human synovium obtained from patients undergoing total knee arthroplasty were FACS sorted, cultured, immunophenotyped and chondrogenically differentiated. The anatomical localization of MPCs in synovium was examined using immunohistochemistry. Finally, the presence of these MPC subsets in healthy synovium obtained from human organ donors was examined. RESULTS: A combination of CD45, CD31, CD73 and CD90 can isolate two distinct MPC-subsets in synovium. These MPC-subsets, freshly isolated from synovium, did not express CD45 or CD31, but expressed CD73. Additionally, a sub-population of CD73+ cells also expressed CD90. CD45-CD31-CD73+CD90- cells were significantly more chondrogenic than CD45-CD31-CD73+CD90+ cells in the presence of TGFß1. Interestingly, reduced chondrogenic ability of CD73+CD90+ cells could be reversed by the addition of BMP2, showing discrete chondrogenic factor requirements by distinct cell-subsets. In addition, these MPCs had distinct anatomical localization; CD73 was expressed both in intimal and sub-intimal region while CD90 was enriched in the sub-intimal region. We further demonstrated that these subsets are also present in healthy synovium. CONCLUSIONS: We provide indications that primary MPCs in synovial intima and sub-intima are phenotypically and functionally distinct with different chondrogenic properties.

Understanding tissue-engineered endochondral ossification; towards improved bone formation.

Endochondral ossification (EO) is the process by which the long bones of the body form and has proven to be a promising method in tissue engineering for achieving cell-mediated bone formation. The present review centred on state-of-the-art research pertaining to mesenchymal stem cells (MSCs)-mediated endochondral bone formation, focusing on the role of donor cells, extracellular matrix and host immune cells during tissue-engineered bone formation. Possible research avenues to improve graft outcome and bone output were highlighted, as well as emerging research that, when applied to tissue-engineered bone grafts, offers new promise for improving the likelihood of such grafts transition from bench to bedside.

Collagen type X is essential for successful mesenchymal stem cell-mediated cartilage formation and subsequent endochondral ossification.

in tissue engineering, endochondral ossification (EO) is often replicated by chondrogenically differentiating mesenchymal stromal cells (MSCs) in vitro and achieving bone formation through in vivo implantation. The resulting marrow-containing bone constructs are promising as a treatment for bone defects. However, limited bone formation capacity has prevented them from reaching their full potential. This is further complicated since it is not fully understood how this bone formation is achieved. Acellular grafts derived from chondrogenically differentiated MSCs can initiate bone formation; however, which component within these decellularised matrices contribute to bone formation has yet to be determined. Collagen type X (COLX), a hypertrophy-associated collagen found within these constructs, is involved in matrix organisation, calcium binding and matrix vesicle compartmentalisation. However, the importance of COLX during tissue-engineered chondrogenesis and subsequent bone formation is unknown. The present study investigated the importance of COLX by shRNA-mediated gene silencing in primary MSCs. A significant knock-down of COLX disrupted the production of extracellular matrix key components and the secretion profile of chondrogenically differentiated MSCs. Following in vivo implantation, disrupted bone formation in knock-down constructs was observed. The importance of COLX was confirmed during both chondrogenic differentiation and subsequent EO in this tissue engineered setting.

Hybridization of Subgap States in One-Dimensional Superconductor-Semiconductor Coulomb Islands.

We present measurements of one-dimensional superconductor-semiconductor Coulomb islands, fabricated by gate confinement of a two-dimensional InAs heterostructure with an epitaxial Al layer. When tuned via electrostatic side gates to regimes without subgap states, Coulomb blockade reveals Cooper-pair mediated transport. When subgap states are present, Coulomb peak positions and heights oscillate in a correlated way with magnetic field and gate voltage, as predicted theoretically, with (anti)crossings in (parallel) transverse magnetic field indicating Rashba-type spin-orbit coupling. Overall results are consistent with a picture of overlapping Majorana zero modes in finite wires.

Injectable BMP-2 delivery system based on collagen-derived microspheres and alginate induced bone formation in a time- and dose-dependent manner.

The aim of the current study was to reduce the clinically used supra-physiological dose of bone morphogenetic protein-2 (BMP-2) (usually 1.5 mg/mL), which carries the risk of adverse events, by using a more effective release system. A slow release system, based on an injectable hydrogel composed of BMP-2-loaded recombinant collagen-based microspheres and alginate, was previously developed. Time- and dose-dependent subcutaneous ectopic bone formation within this system and bone regeneration capacity in a calvarial defect model were investigated. BMP-2 doses of 10 µg, 3 µg and 1 µg per implant (50 µg/mL, 15 µg/mL and 5 µg/mL, respectively) successfully induced ectopic bone formation subcutaneously in rats in a time- and dose-dependent manner, as shown by micro-computed tomography (µCT) and histology. In addition, the spatio-temporal control of BMP-2 retention was shown for 4 weeks in vivo by imaging of fluorescently-labelled BMP-2. In the subcritical calvarial defect model, µCT revealed a higher bone volume for the 2 µg of BMP-2 per implant condition (50 µg/mL) as compared to the lower dose used (0.2 µg per implant, 5 µg/mL). Complete defect bridging was obtained with 50 µg/mL BMP-2 after 8 weeks. The BMP-2 concentration of 5 µg/mL was not sufficient to heal a calvarial defect faster than the empty defect or biomaterial control without BMP-2. Overall, this injectable BMP-2 delivery system showed promising results with 50 µg/mL BMP-2 in both the ectopic and calvarial rat defect models, underling the potential of this composite hydrogel for bone regeneration therapies.

Preclinical Pharmacology in the Rhesus Monkey of CW 1759-50, a New Ultra-short Acting Nondepolarizing Neuromuscular Blocking Agent, Degraded and Antagonized by L-Cysteine.

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Structure-activity studies were performed to identify a new neuromuscular blocking agent retaining the ultra-short acting characteristics of gantacurium, including degradation and reversal by L-cysteine, but lacking its histaminoid properties in man. CW 1759-50 has emerged from this program. METHODS: Adduction of CW 1759-50 with L-cysteine was studied by high-performance liquid chromatography and mass spectrometry. Institutional Animal Care and Use Committee-approved comparisons of CW 1759-50 to gantacurium were performed in rhesus monkeys. ED95 for neuromuscular blockade was established. Spontaneous recovery was compared to reversal by L-cysteine in paired studies of boluses or infusions. In addition, changes in mean arterial pressure and heart rate after very large doses of 15 to 60 × ED95 were compared. RESULTS: The half-time of adduction of L-cysteine to CW 1759-50 in vitro was 2.3 min. The ED95 of CW 1759-50 was 0.069 ± 0.02 mg/kg; ED95 of gantacurium was 0.081 ± 0.05 mg/kg (P = 0.006). Duration of action (recovery to 95% twitch height after 98 to 99% blockade) was as follows: CW 1759-50, 8.2 ± 1.5 min; and gantacurium, 7.4 ± 1.9 min; (n = 8 and 9, P = 0.355). Administration of L-cysteine (30 mg/kg) shortened recovery (i.e., induced reversal) from CW 1759-50 after boluses or infusions (P always less than 0.0001). Recovery intervals (5 to 95% twitch) ranged from 6.1 to 6.7 min (and did not differ significantly) after boluses of 0.10 to 0.50 mg/kg, as well as control infusions (P = 0.426 by analysis of variance). Dose ratios comparing changes of 30% in mean arterial pressure or heart rate to ED95 for neuromuscular blockade (ED 30% Δ [mean arterial pressure or heart rate]/ED95) were higher for CW 1759-50 than for gantacurium. CONCLUSIONS: CW 1759-50, similar to gantacurium, is an ultra-short acting neuromuscular blocking agent, antagonized by L-cysteine, in the monkey. The circulatory effects, however, are much reduced in comparison with gantacurium, suggesting a trial in humans.

Mesenchymal stem cell-mediated endochondral ossification utilising micropellets and brief chondrogenic priming.

With limited autologous and donor bone graft availability, there is an increasing need for alternative graft substitutes. We have previously shown that chondrogenically priming mesenchymal stem cell (MSC) pellets for 28 d in vitro will reproducibly result in endochondral bone formation after in vivo implantation. However, pellet priming time for clinical applications is quite extensive. A micropellet (µpellet)-fibrin construct was developed and coupled, with a shorter priming period, determined by an in vitro time course experiment. In vitro data showed expression of chondrogenic genes and matrix production after 7 d of chondrogenic priming, indicating that briefer priming could possibly be used to induce bone formation in vivo. 7 and 28 d primed pellet, pellet-fibrin and µpellet-fibrin constructs were cultured for in vitro analysis and implanted subcutaneously for 8 weeks into nude mice. µpellet-fibrin constructs, cultured in vitro for 7 or 28 d, produced comparable bone to standard pellets in vivo. MSC-mediated bone formation was achieved following only 7 d of in vitro priming. Bone formation in vivo appeared to be influenced by overall matrix production pre-implantation. Given this short priming time and the injectable nature of the µpellet-fibrin constructs, this approach might be further developed as an injectable bone substitute, leading to a minimally-invasive treatment option, which would allow for tailored filling of bone defects.

Rashba Interaction and Local Magnetic Moments in a Graphene-BN Heterostructure Intercalated with Au.

We intercalate a van der Waals heterostructure of graphene and hexagonal boron nitride with Au, by encapsulation, and show that the Au at the interface is two dimensional. Charge transfer upon current annealing indicates the redistribution of the Au and induces splitting of the graphene band structure. The effect of an in-plane magnetic field confirms that the splitting is due to spin splitting and that the spin polarization is in the plane, characteristic of a Rashba interaction with a magnitude of approximately 25 meV. Consistent with the presence of an intrinsic interfacial electric field we show that the splitting can be enhanced by an applied displacement field in dual gated samples. A giant negative magnetoresistance, up to 75%, and a field induced anomalous Hall effect at magnetic fields <1 T are observed. These demonstrate that the hybridized Au has a magnetic moment and suggests the proximity to the formation of a collective magnetic phase. These effects persist close to room temperature.

Quantum Transport Detected by Strong Proximity Interaction at a Graphene-WS2 van der Waals Interface.

Magnetotransport measurements demonstrate that graphene in a van der Waals heterostructure is a sensitive probe of quantum transport in an adjacent WS2 layer via strong Coulomb interactions. We observe a large low-field magnetoresistance (≫ e(2)/h) and a -ln T temperature dependence of the resistance. In-plane magnetic field resistance indicates the origin is orbital and nonclassical. We demonstrate a strong electron-hole asymmetry in the mobility and coherence length of graphene demonstrating the presence of localized Coulomb interactions with ionized donors in the WS2 substrate, which ultimately leads to screening as the Fermi level of graphene is tuned toward the conduction band of WS2. This leads us to conclude that graphene couples to quantum localization processes in WS2 via the Coulomb interaction and results in the observed signatures of quantum transport. Our results show that theoretical descriptions of the van der Waals interface should not ignore localized strong correlations.

Biological data from a data-deficient shark: the Arabian smoothhound Mustelus mosis (Carcharhiniformes: Triakidae).

The present study provides information on length distribution, reproductive biology and diet of Mustelus mosis based on individuals caught in waters off the eastern Arabian Peninsula. Although ageing of vertebral centra was attempted, band pairs were of low clarity and counts could not be confidently assigned.

Seasonal migration of the starry smooth-hound shark Mustelus asterias as revealed from tag-recapture data of an angler-led tagging programme.

The primary aim of this long-term angler-led tagging programme was to gain information about seasonal changes in distribution of the starry smooth-hound shark Mustelus asterias, along the Dutch coast for management and conservation purposes. Between 2011 and 2014, M. asterias comprised 92·6% (n = 2418) of the total elasmobranch catch (n = 2612) by the licenced group of taggers within the Dutch Delta of which 2244 M. asterias were fin-tagged with plastic rototags. Sex and total length (LT ) composition inside the eastern tidal basin (Oosterschelde) were significantly different, i.e. more females and larger individuals, than outside indicating a pupping ground, which was confirmed by the capture of 30 newborn pups (≤32 cm). The distribution pattern of reported recaptured M. asterias (return-rate 3·6%, n = 80) showed a circannual migration between summering in the southern North Sea and wintering in the English Channel and the Bay of Biscay, and suggests that M. asterias is philopatric. The Dutch angling season for M. asterias runs from approximately mid-May to mid-October when the water temperature is above 13° C. Recaptures of eight mature females, but no males in the Bay of Biscay, indicate partial spatial segregation by sex, where mature females migrate over larger distances than immature females and males. These observations, with the absence of recaptures in other known summering areas (i.e. the Irish Sea and Bristol Channel), suggest that the southern North Sea is used by a separate population. Implications for management and recommendations to improve and expand the study approach are discussed.

Human osteoarthritic synovium impacts chondrogenic differentiation of mesenchymal stem cells via macrophage polarisation state.

OBJECTIVE: Mesenchymal stem cells (MSCs) are a promising cell type for the repair of damaged cartilage in osteoarthritis (OA). However, OA synovial fluid and factors secreted by synovium impede chondrogenic differentiation of MSCs, and the mechanism responsible for this effect remains unclear. In this study, we sought to investigate whether M1 and M2 synovial macrophages can contribute to the inhibition of MSC chondrogenesis. DESIGN: The constitution of synovial macrophage subsets was analysed by immunohistochemical staining of human OA synovium sections for CD86 (M1 marker) and CD206 (M2 marker). To assess the effect of synovial macrophages on chondrogenesis, collagen type II (COL2) and aggrecan (ACAN) gene expression were compared between MSCs undergoing chondrogenic differentiation in medium conditioned (CM) by human OA synovial explants, human synovial macrophages and fibroblasts, or peripheral blood derived primary human monocytes differentiated towards an M1 or M2 phenotype. RESULTS: OA synovium contained both M1 and M2 macrophages. Medium conditioned by synovial macrophages (CD45 + plastic adherent cells) down-regulated chondrogenic gene expression by MSCs. Additionally, CM of M1 polarised monocytes significantly decreased COL2 and ACAN gene expression by MSCs; this effect was not observed for treatment with CM of M2 polarised monocytes. CONCLUSION: MSC chondrogenesis is inhibited by OA synovium CM through factors secreted by synovial macrophages and our findings suggest that M1 polarised subsets are potential mediators of this anti-chondrogenic effect. Modulation of macrophage phenotype may serve as a beneficial strategy to maximise the potential of MSCs for efficient cartilage repair.

Apparent rate constant mapping using hyperpolarized [1-(13)C]pyruvate.

Hyperpolarization of [1-13C]pyruvate in solution allows real-time measurement of uptake and metabolism using MR spectroscopic methods. After injection and perfusion, pyruvate is taken up by the cells and enzymatically metabolized into downstream metabolites such as lactate, alanine, and bicarbonate. In this work, we present comprehensive methods for the quantification and interpretation of hyperpolarized 13C metabolite signals. First, a time-domain spectral fitting method is described for the decomposition of FID signals into their metabolic constituents. For this purpose, the required chemical shift frequencies are automatically estimated using a matching pursuit algorithm. Second, a time-discretized formulation of the two-site exchange kinetic model is used to quantify metabolite signal dynamics by two characteristic rate constants in the form of (i) an apparent build-up rate (quantifying the build-up of downstream metabolites from the pyruvate substrate) and (ii) an effective decay rate (summarizing signal depletion due to repetitive excitation, T1-relaxation and backward conversion). The presented spectral and kinetic quantification were experimentally verified in vitro and in vivo using hyperpolarized [1-13C]pyruvate. Using temporally resolved IDEAL spiral CSI, spatially resolved apparent rate constant maps are also extracted. In comparison to single metabolite images, apparent build-up rate constant maps provide improved contrast by emphasizing metabolically active tissues (e.g. tumors) and suppression of high perfusion regions with low conversion (e.g. blood vessels). Apparent build-up rate constant mapping provides a novel quantitative image contrast for the characterization of metabolic activity. Its possible implementation as a quantitative standard will be subject to further studies.

Effects of hyperbaric oxygen therapy on the viability of irradiated soft head and neck tissues in mice.

OBJECTIVES: Hyperbaric oxygen therapy (HBOT) is used clinically in irradiation-induced injury to healthy tissues, but the effectiveness and working mechanism remain unclear. This study examined the effects of HBOT on irradiated salivary glands and tongue in a mouse model. MATERIALS AND METHODS: Mice were irradiated with a single dose (15 Gy) in the head and neck region and subjected to HBOT, either before or after irradiation. During the course of the treatments, salivary flow rates were measured and at different time points after radiation (2, 6, 10 and 24 weeks), salivary glands and tongue were harvested and (immuno) histochemically analysed. RESULTS: Proliferation and blood vessel density in salivary glands were enhanced by HBOT in the medium term (10 weeks after irradiation), while salivary flow rates were not influenced. In the long term, irradiation-induced proliferation in the muscle tissue of the tongue was decreased by HBOT. CONCLUSION: Hyperbaric oxygen therapy (HBOT) appears to stimulate regeneration or protection of salivary gland tissue following radiation therapy. Possible implications of the effect of HBOT on muscle tissue of the tongue for the prevention of dysphagia and trismus are discussed. This study provides insights on the cellular changes after HBOT and encourages further research on this topic to achieve a better implementation of the therapy in humans.

Patient perceptions of success in obesity treatment: An IMI2 SOPHIA study.

Background: It is anticipated that by 2030, 20% of the world's population will live with obesity. Success in the management of obesity is predominately determined in terms of BMI or percentage weight loss, yet the limitations of these have been widely recognized. This study aimed to understand patient definitions of success in obesity treatment. Methods: A series of in-depth focus groups, carried out with n = 30 adults living with obesity, offered a qualitative insight into patient definitions of success. Results: A thematic analysis of data yielded four thematic findings: Success as freedom from stigma, bias and the mental burden of obesity; success as being able to participate fully in the world; success as measured by NSVs [non-scale victories]; and success is not a number on a scale. Conclusions: What this study highlights is (1) how current measures of success do not accurately encompass the priorities of people living with obesity, (2) the importance of addressing the psychological and emotional aspects of living with obesity in any definition of success , and (3) the importance of meaningful co-creation of goals and indicators of success between clinician and patient for the effective management of the disease of obesity.

The Tandem VR™ protocol: Synchronized nature-based and other outdoor experiences in virtual reality for hospice patients and their caregivers.

Background: Nature-based and other outdoor virtual reality (VR) experiences in head-mounted displays (HMDs) offer powerful, non-pharmacological tools for hospice teams to help patients undergoing end-of-life (EOL) transitions. However, the psychological distress of the patient-caregiver dyad is interconnected and highlights the interdependence and responsiveness to distress as a unit. Hospice care services and healthcare need strategies to help patients and informal caregivers with EOL transitions. Methods: Our study uses the synchronized Tandem VR TM approach where patient-caregiver dyads experience immersive nature-based and other outdoor VR content. This mixed methods study will recruit 20 patient-caregiver dyads (N = 40) enrolled in home hospice services nearing EOL. Dyads will experience a personalized nature-based and other outdoor VR experience lasting 5-15 min. Self-reported questionnaires and semi-structured interviews will be collected pre/post the VR intervention to identify the impacts of Tandem VR TM experiences on the QOL, pain, and fear of death in patient-caregiver dyads enrolled with hospice services. Additionally, this protocol will determine the acceptance of Tandem VR TM experiences by dyads as a non-pharmacological modality for addressing patient and caregiver needs. Acceptance will be quantified by the number of dyads accepting or declining the VR experience during recruitment. Discussion: Using personalized, nature-based and other outdoor VR content, the patient-caregiver dyads can simultaneously engage in an immersive encounter may help alleviate symptoms associated with declining health and EOL phases for the patient and the often overburdened caregiver. This protocol focuses on meeting the need for person-centered, non-pharmacological interventions to reduce physical, psychological, and spiritual distress. Trial registration: NCT06186960.

Case Report: Resolution of high grade anal squamous intraepithelial lesion with antibiotics proposes a new role for syphilitic infection in potentiation of HPV-associated ASCC.

Introduction: Human Papillomavirus (HPV) is the primary risk factor for the development of anal intraepithelial neoplasia (AIN) and is a leading risk factor for anogenital squamous cell carcinoma (ASCC). Despite common shared risk factors for both HPV and syphilis, co-infection is not well documented, and the role of syphilitic infection in HPV-associated AIN and ASCC potentiation is not defined. Case description/methods: A 72-year-old single male presented with complaints of mild rectal pain and intermittent rectal bleeding. A flexible sigmoidoscopy was performed, and a firm 4.5cm x 3cm perianal mass was detected and superficially biopsied. Pathology findings demonstrated evidence of a high grade squamous intraepithelial lesion (HGSIL, AIN II/III/AIS) with viral cytopathic effect, consistent with HPV infection. Much of the biopsied lesion showed acanthotic squamous mucosa with intraepithelial neutrophils and abundant submucosal plasma cells, suggesting possible syphilitic involvement. Subsequent immunohistochemical staining for p16 as a surrogate marker for HPV was positive, as was an immunohistochemical stain for spirochetes, supportive of co-infection with Treponema pallidum pallidum (T. pallidum), the causative agent in venereal syphilis. The patient was referred to an infectious disease specialist for syphilitic infection and was treated with penicillin with surprisingly complete resolution of the lesion. EUAs were performed 2- and 3-months following treatment without lesion recurrence. However, one year following diagnosis, a flexible sigmoidoscopy revealed a 5 mm recurrent HPV-related low-grade AIN 1 lesion at the dentate line. Discussion: Resolution of the lesion by antibiotic treatment for syphilitic infection suggested that co-infection by T. pallidum may potentiate HPV-associated squamous cell carcinoma based on histological findings. Findings from this case, as well as a review of bacterial involvement and potentiation in various cancers, are reviewed here. Such findings offer new insight regarding the role of STI-associated bacteria and HPV co-infection in the establishment of AIN and may additionally propose new treatment modalities for ASCC.