Search

We propose an optimization algorithm to generate a robust magnetic force against position error to achieve good controllability of the magnetic robot in the region of interest of a magnetic navigation system comprising electromagnets. We formulate an optimization problem that minimizes the norm of the spatial derivatives of the magnetic force subject to the constraints of the magnetic flux density and magnetic force. The robust magnetic force generated by the proposed algorithm was compared with conventional pseudo-inverse matrix method and verified through an experiment in which a magnetic robot was successfully steered along a bifurcated glass tube to reach a target position.

We developed a resonance control method to generate a high-speed rotating magnetic field in a three-phase magnetic navigation system composed of three electromagnets. The proposed resonance control method calculates the amplitudes and phases of voltages, while the capacitances suppressing the self and mutual inductances of the electromagnets to keep the currents and the magnitude of the rotating magnetic field constant, even if the frequency of the rotating magnetic field increases. Finally, we prototyped the three-phase magnetic navigation system and the variable capacitor module to validate the effectiveness of the proposed resonance control method experimentally.

We propose a novel position control method (PCM) for the Robotically Assisted MAgnetic Navigation (RAMAN) system to improve the pushability of the magnetic catheter (MC) by maximizing the magnetic force. We expressed the magnetic force acting on the magnetic catheter as the position and the current flowing through each of the electromagnets of the RAMAN system. Next, we formulated a PCM as an optimization problem to maximize the MF. From the proposed PCM, we can determine the position that generates the maximum MF in the desired direction within the region of interest of the RAMAN as well as the required applied current of each electromagnet. Finally, we performed a navigation experiment for the MC along the aorta to the right coronary artery in a cardiac vascular phantom model, and we showed that the proposed PCM can navigate through the vascular phantom effectively without buckling of the MC.

Helical magnetic robots driven by an external magnetic field have been extensively studied for robotic endovascular intervention to treat occlusive vascular disease. Most previous researchers have utilized cone-shaped head helical magnetic robots (CHMRs) with helical blades for thrombus drilling. However, the CHMR may become stuck in the thrombus or drilling performance may be significantly reduced after the cone-shape head enters the thrombus. We propose a sawtooth head helical magnetic robot (SHMR) to improve drilling performance. Furthermore, the pitch length of the SHMR was optimized experimentally. Finally, improved drilling performance of the SHMR compared to CHMR was verified by in vitro drilling experiments with a pseudo thrombus containing 0.8 wt. %, 1.0 wt. %, and 1.2 wt. % agar.

ABSTRACT Pediatric community-acquired pneumonia (CAP) is often treated with 10 days of antibiotics. Shorter treatment strategies may be effective and lead to less resistance. The impact of duration of treatment on the respiratory microbiome is unknown. Data are from children (n = 171), ages 6 to 71 months, enrolled in the SCOUT-CAP trial (NCT02891915). Children with CAP were randomized to a short (5 days) versus standard (10 days) beta-lactam treatment strategy. Throat swabs were collected at enrollment and the end of the study and used for shotgun metagenomic sequencing. The number of beta-lactam and multidrug efflux resistance genes per prokaryotic cell (RGPC) was significantly lower in children receiving the short compared to standard treatment strategy at the end of the study (Wilcoxon rank sum test, P

Abstract High quality Ge doping of GaN is demonstrated using primarily thermal neutrons for the first time. In this study, GaN was doped with Ge to concentrations from 1016 Ge atoms/cm3 to 1018 Ge atoms/cm3. The doping concentrations were measured using gamma-ray spectroscopy and confirmed using SIMS analysis. The data from SIMS analysis also show consistent Ge doping concentration throughout the depth of the GaN wafers. After irradiation, the GaN was annealed in a nitrogen environment at 950 °C for 30 min. The neutron doping process turns out to produce spatially uniform doping throughout the whole volume of the GaN substrate.

MXenes are two-dimensional (2D) transition metal carbides, nitrides, and carbonitrides with unique intrinsic properties, including excellent electrical conductivity, 2D sheet morphology, lightweight, flexibility, tunable surface chemistry, and easy solution processability, thus attracting considerable attention as electromagnetic interference (EMI) shielding materials. In this review, we demonstrate, from both experimental and theoretical perspectives, that the outstanding EMI shielding performance of MXenes is determined not only by its intrinsic properties but also by extrinsic modifications such as the introduction of dielectric inclusions, pores, or other designed structures. This review provides guidance for the efficient application of available resources, as well as insights into the challenges that should be addressed to develop more efficient and economical MXene based shielding materials for the advanced electronics industry of the future.

Abstract We present a measurement of the ratio R μ = B τ − → μ − ν ¯ μ ν τ / B τ − → e − ν ¯ e ν τ $$ {R}_{\mu }=\mathcal{B}\left({\tau}^{-}\to {\mu}^{-}{\overline{\nu}}_{\mu }{\nu}_{\tau}\right)/\mathcal{B}\left({\tau}^{-}\to {e}^{-}{\overline{\nu}}_e{\nu}_{\tau}\right) $$ of branching fractions B $$ \mathcal{B} $$ of the τ lepton decaying to muons or electrons using data collected with the Belle II detector at the SuperKEKB e + e − collider. The sample has an integrated luminosity of 362 ± 2 fb −1 at a centre-of-mass energy of 10.58 GeV. Using an optimised event selection, a binned maximum likelihood fit is performed using the momentum spectra of the electron and muon candidates. The result, R μ = 0.9675 ± 0.0007 ± 0.0036, where the first uncertainty is statistical and the second is systematic, is the most precise to date. It provides a stringent test of the light-lepton universality, translating to a ratio of the couplings of the muon and electron to the W boson in τ decays of 0.9974 ± 0.0019, in agreement with the standard model expectation of unity.

Abstract We present measurements of the branching fractions of eight B ¯ 0 $$ {\overline{B}}^0 $$ → D (*)+ K − K S ∗ 0 $$ {K}_{(S)}^{\left(\ast \right)0} $$ , B − → D (*)0 K − K S ∗ 0 $$ {K}_{(S)}^{\left(\ast \right)0} $$ decay channels. The results are based on data from SuperKEKB electron-positron collisions at the Υ(4S) resonance collected with the Belle II detector, corresponding to an integrated luminosity of 362 fb −1. The event yields are extracted from fits to the distributions of the difference between expected and observed B meson energy, and are efficiency-corrected as a function of m(K − K S ∗ 0 $$ {K}_{(S)}^{\left(\ast \right)0} $$ ) and m(D (*) K S ∗ 0 $$ {K}_{(S)}^{\left(\ast \right)0} $$ ) in order to avoid dependence on the decay model. These results include the first observation of B ¯ 0 $$ {\overline{B}}^0 $$ → D + K − K S 0 $$ {K}_S^0 $$ , B − → D* 0 K − K S 0 $$ {K}_S^0 $$ , and B ¯ 0 $$ {\overline{B}}^0 $$ → D* + K − K S 0 $$ {K}_S^0 $$ decays and a significant improvement in the precision of the other channels compared to previous measurements. The helicity-angle distributions and the invariant mass distributions of the K − K S ∗ 0 $$ {K}_{(S)}^{\left(\ast \right)0} $$ systems are compatible with quasi-two-body decays via a resonant transition with spin-parity J P = 1− for the K − K S 0 $$ {K}_S^0 $$ systems and J P = 1+ for the K − K* 0 systems. We also present measurements of the branching fractions of four B ¯ 0 $$ {\overline{B}}^0 $$ → D (*)+ D s − $$ {D}_s^{-} $$ , B − → D (*)0 D s − $$ {D}_s^{-} $$ decay channels with a precision compatible to the current world averages.

Abstract We present a search for the charged lepton-flavor-violating decays ϒ(1S) → ℓ ± ℓ′∓ and radiative charged lepton-flavour-violating decays ϒ(1S) → γ ℓ ± ℓ′∓ [ℓ,ℓ′ = e, μ, τ] using the 158 million ϒ(2S) sample collected by the Belle detector at the KEKB collider. This search uses ϒ(1S) mesons produced in ϒ(2S) → π + π − ϒ(1S) transitions. We do not find any significant signal, so we provide upper limits on the branching fractions at the 90% confidence level.

Abstract We present the first measurement of the branching fraction of the singly Cabibbo-suppressed (SCS) decay Λ c + $$ {\Lambda}_c^{+} $$ → pη′ with η′ → ηπ + π − , using a data sample corresponding to an integrated luminosity of 981 fb −1, collected by the Belle detector at the KEKB e + e − asymmetric-energy collider. A significant Λ c + $$ {\Lambda}_c^{+} $$ → pη′ signal is observed for the first time with a signal significance of 5.4σ. The relative branching fraction with respect to the normalization mode Λ c + $$ {\Lambda}_c^{+} $$ → pK − π + is measured to be B Λ c + → pη ′ B Λ c + → pK − π + = 7.54 ± 1.32 ± 0.73 × 10 − 3 , $$ \frac{\mathcal{B}\left({\Lambda}_c^{+}\to p\eta^{\prime}\right)}{\mathcal{B}\left({\Lambda}_c^{+}\to {pK}^{-}{\pi}^{+}\right)}=\left(7.54\pm 1.32\pm 0.73\right)\times {10}^{-3}, $$ where the uncertainties are statistical and systematic, respectively. Using the world-average value of B Λ c + → pK − π + $$ \mathcal{B}\left({\Lambda}_c^{+}\to {pK}^{-}{\pi}^{+}\right) $$ = (6.28 ± 0.32) × 10 −2, we obtain B Λ c + → pη ′ = 4.73 ± 0.82 ± 0.46 ± 0.24 × 10 − 4 , $$ \mathcal{B}\left({\Lambda}_c^{+}\to p\eta^{\prime}\right)=\left(4.73\pm 0.82\pm 0.46\pm 0.24\right)\times {10}^{-4}, $$ where the uncertainties are statistical, systematic, and from B Λ c + → pK − π + $$ \mathcal{B}\left({\Lambda}_c^{+}\to {pK}^{-}{\pi}^{+}\right) $$ , respectively.

In the present study, a high-order high-resolution energy stable weighted essentially non-oscillatory plus (ESWENO-P) scheme was developed by improving the weighting function in the energy stable weighted essentially non-oscillatory (ESWENO) scheme. First, the weighting function was modified by introducing a new user-defined parameter. Then, the fine-tuning term in the weighted essentially non-oscillatory-Z plus (WENO-ZP) scheme was adopted to the modified weighting function. A parametric study was conducted to determine the value of the user-defined parameter included in the fine-tuning term. To validate the accuracy and the resolution of the present ESWENO-P scheme, well known one- and two-dimensional benchmark flow problems involving shocks and vortices were tested. It was found that, compared to the ESWENO, the present ESWENO-P scheme is more stable near strong discontinuities. It was also observed that, compared to the WENO-ZP, the present ESWENO-P scheme was less sensitive to the user-defined parameter included in the fine-tuning term. Overall, compared to the existing weighted essentially non-oscillatory (WENO) family schemes, the present ESWENO-P scheme consistently resolves flows with high resolution without much computational overhead.

Abstract We examined the effect of ice‐binding protein derived from Leucosporidium (LeIBP) on the cryopreservation of bull semen and compared it with that derived from previously reported Antifreeze Protein III (AFPIII). Six concentrations of LeIBP (10–1 ~ 104 μg/ml) and AFPIII (10–1 ~ 104 μg/ml) were added to the bull semen extender, respectively. Sperm kinematic parameters were measured to examine sperm toxicity and cryopreserved sperm quality. Measures of antioxidant activity such as superoxide dismutase (SOD), reduced glutathione/oxidative glutathione (GSH/GSSG), and total antioxidant capacity (TAC) were analysed to identify the effect of LeIBP on sperm quality. In addition, sperm viability was analysed using a flow cytometer and fluorescence microscope by SYBR14/PI staining. The results showed that the LeIBP groups (0.1, 1 and 10 μg/ml) were less toxic, and the quality of the sperm were dramatically improved in the extenders containing 0.1 μg/ml LeIBP among concentrations of LeIBP and AFPIII. The SOD activity of LeIBP was greater than that of AFPIII and control. In addition, sperm viability was enhanced in the LeIBP‐treated group. In summary, LeIBP is a useful cryoprotective adjuvant for bull sperm cryopreservation, and the most efficient concentration of LeIBP is 0.1 μg/ml.

Abstract The first dedicated search for the η c2(1D) is carried out using the decays B + → η c2(1D)K +, B 0 → η c2(1D) K S 0 $$ {K}_S^0 $$ , B 0 → η c2(1D)π − K +, and B + → η c2(1D)π + K S 0 $$ {K}_S^0 $$ with η c2(1D) → h c γ. No significant signal is found. For the η c2(1D) mass range between 3795 and 3845 MeV/c 2, the branching-fraction upper limits are determined to be ℬ(B + → η c2(1D)K +) × ℬ(η c2(1D) → h c γ) < 3.7 × 10 −5, ℬ(B 0 → η c2(1D)K 0) × ℬ(η c2(1D) → h c γ) < 3.5 × 10 −5, ℬ(B 0 → η c2(1D)π − K +) × ℬ(η c2(1D) → h c γ) < 1.0 × 10 −4, and ℬ(B + → η c2(1D)π + K S 0 $$ {K}_S^0 $$ ) × ℬ(η c2(1D) → h c γ) < 1.1 × 10 −4 at 90% C.L. The analysis is based on the 711 fb −1 data sample collected on the ϒ(4S) resonance by the Belle detector, which operated at the KEKB asymmetric-energy e + e − collider.

Abstract We present the first model-independent measurement of the CKM unitarity triangle angle ϕ 3 using B ± → D( K S 0 $$ {K}_{\mathrm{S}}^0 $$ π + π − π 0) K ± decays, where D indicates either a D 0 or D ¯ $$ \overline{D} $$ 0 meson. Measurements of the strong-phase difference of the D → K S 0 $$ {K}_{\mathrm{S}}^0 $$ π + π − π 0 amplitude obtained from CLEO-c data are used as input. This analysis is based on the full Belle data set of 772 × 106 B B ¯ $$ \overline{B} $$ events collected at the Υ(4S) resonance. We obtain ϕ 3 = ( 5.7 − 8.8 + 10.2 $$ {5.7}_{-8.8}^{+10.2} $$ ±3.5±5.7) ° and the suppressed amplitude ratio r B = 0.323±0.147±0.023±0.051. Here the first uncertainty is statistical, the second is the experimental systematic, and the third is due to the precision of the strong-phase parameters measured from CLEO-c data. The 95% confidence interval on ϕ 3 is (−29.7, 109.5) ° , which is consistent with the current world average.

MicroRNAs (miRNA) are small non-coding RNAs (∼22 nt in length) that are known as potent master regulators of eukaryotic gene expression. miRNAs have been shown to play a critical role in cancer pathogenesis, and the misregulation of miRNAs is a well-known feature of cancer. In recent years, miR-29 has emerged as a critical miRNA in various cancers, and it has been shown to regulate multiple oncogenic processes, including epigenetics, proteostasis, metabolism, proliferation, apoptosis, metastasis, fibrosis, angiogenesis, and immunomodulation. Although miR-29 has been thoroughly documented as a tumor suppressor in the majority of studies, some controversy remains with conflicting reports of miR-29 as an oncogene. In this review, we provide a systematic overview of miR-29’s functional role in various mechanisms of cancer and introspection on the contradictory roles of miR-29.

Rationale: Baclofen is a commonly prescribed medication used to decrease spasticity in children with cerebral palsy. Despite its widespread use, this medication has not demonstrated to be consistently effective in clinical studies. Baclofen is also associated with systemic adverse effects due to potent neuronal depression. The management of baclofen toxicity is mainly supportive; however, some studies have shown that hemodialysis may alleviate the symptoms of an overdose and shorten the recovery time. Presenting concerns: In this case report, a 6-year-old boy with mild cerebral palsy, neuromyelitis optica, and normal kidney function was found unresponsive at home, with altered mental status, after ingesting 1300 mg of baclofen unobserved. The patient was intubated and mechanically ventilated because of significant neurologic depression with subsequent respiratory failure. Diagnosis: The patient was diagnosed with baclofen-induced encephalopathy. An elevated serum baclofen level of 4.00 µg/mL (therapeutic range of 0.08-0.40 µg/mL) was observed 10 hours after he was found unresponsive. The patient’s respiratory status deteriorated; he had high ventilatory requirements and remained comatose. Intervention: With the worsening of his clinical condition in the intensive care unit, hemodialysis, administered via a high-efficiency high-flux dialyzer, was initiated approximately 18 hours after he was found unresponsive. The patient underwent 2 hemodialysis runs spaced 9 hours apart, with blood flow rates approaching 250 mL/min. Outcomes: Within 3 hours of the first hemodialysis treatment, the patient started to regain consciousness. He was extubated to room air 6 hours after the second hemodialysis treatment. Novel findings: Supportive management is the primary treatment of baclofen toxicity in a pediatric patient with normal kidney function. Hemodialysis may be considered in severe cases of baclofen toxicity and worsening clinical status, but further studies are needed to confirm this finding.

Abstract We report evidence for the charged charmed-strange baryon $$\Xi _{c}(2930)^+$$ Ξc(2930)+ with a signal significance of 3.9$$\sigma $$ σ with systematic errors included. The charged $$\Xi _{c}(2930)^+$$ Ξc(2930)+ is found in its decay to $$K_{S}^{0} \Lambda _{c}^+$$ KS0Λc+ in the substructure of $$\bar{B}^{0} \rightarrow K^{0}_{S} \Lambda _{c}^{+} \bar{\Lambda }_{c}^{-}$$ B¯0→KS0Λc+Λ¯c- decays. The measured mass and width are $$[2942.3 \pm 4.4 ({\mathrm{stat.}}) \pm {1.5}({\mathrm{syst.}})]$$ [2942.3±4.4(stat.)±1.5(syst.)] MeV/$$c^{2}$$ c2 and $$[14.8 \pm 8.8({\mathrm{stat.}}) \pm {2.5}({\mathrm{syst.}})]$$ [14.8±8.8(stat.)±2.5(syst.)] MeV, respectively, and the product branching fraction is $$\mathcal{B}(\bar{B}^{0} \rightarrow \Xi _c(2930)^{+} \bar{\Lambda }_{c}^{-}) \mathcal{B}(\Xi _c(2930)^{+}\rightarrow \bar{K}^{0} \Lambda _{c}^{+})=[2.37 \pm 0.51 ({\mathrm{stat.}})\pm 0.31({\mathrm{syst.}})]\times 10^{-4}$$ B(B¯0→Ξc(2930)+Λ¯c-)B(Ξc(2930)+→K¯0Λc+)=[2.37±0.51(stat.)±0.31(syst.)]×10-4 . We also measure $$\mathcal{B}(\bar{B}^{0} \rightarrow \bar{K}^{0} \Lambda _{c}^{+} \bar{\Lambda }_{c}^{-}) = [3.99 \pm 0.76({\mathrm{stat.}}) \pm 0.51({\mathrm{syst.}})] \times 10^{-4}$$ B(B¯0→K¯0Λc+Λ¯c-)=[3.99±0.76(stat.)±0.51(syst.)]×10-4 with greater precision than previous experiments, and present the results of a search for the charmonium-like state Y(4660) and its spin partner, $$Y_{\eta }$$ Yη , in the $$\Lambda _{c}^{+}\bar{\Lambda }_{c}^{-}$$ Λc+Λ¯c- invariant mass spectrum. No clear signals of the Y(4660) or $$Y_{\eta }$$ Yη are observed and the 90% credibility level (C.L.) upper limits on their production rates are determined. These measurements are obtained from a sample of $$(772\pm 11)\times 10^{6} B\bar{B}$$ (772±11)×106BB¯ pairs collected at the $$\Upsilon (4S)$$ Υ(4S) resonance by the Belle detector at the KEKB asymmetric energy electron-positron collider.

Abstract We study bottomonium production in association with an $$\eta $$ η meson in $$e^+e^-$$ e+e- annihilations near the $$\varUpsilon (5S)$$ Υ(5S) , at a centre-of-mass energy of $$\sqrt{s}=10.866$$ s=10.866 GeV. The results are based on the 121.4 fb$$^{-1}$$ -1 data sample collected by the Belle experiment at the asymmetric-energy KEKB collider. Only the $$\eta $$ η meson is reconstructed and the missing-mass spectrum of $$\eta $$ η candidates is investigated. We observe the $$e^+e^-\rightarrow \eta \varUpsilon _J(1D)$$ e+e-→ηΥJ(1D) process and find evidence for the $$e^+e^-\rightarrow \eta \varUpsilon (2S)$$ e+e-→ηΥ(2S) process, while no significant signals of $$\varUpsilon (1S)$$ Υ(1S) , $$h_b(1P)$$ hb(1P) , nor $$h_b(2P)$$ hb(2P) are found. Cross sections for the studied processes are reported.

Wetlands of northern high latitudes are ecosystems highly vulnerable to climate change. Some degradation effects include soil hydrologic changes due to permafrost thaw, formation of deeper active layers, and rising topsoil temperatures that accelerate the degradation of permafrost carbon and increase in CO2 and CH4 emissions. In this work we present 2 years of modeled year-round CH4 emissions into the atmosphere from a Northeast Siberian region in the Russian Far East. We use a revisited version of the process-based JSBACH-methane model that includes four CH4 transport pathways: plant-mediated transport, ebullition and molecular diffusion in the presence or absence of snow. The gas is emitted through wetlands represented by grid cell inundated areas simulated with a TOPMODEL approach. The magnitude of the summertime modeled CH4 emissions is comparable to ground-based CH4 fluxes measured with the eddy covariance technique and flux chambers in the same area of study, whereas wintertime modeled values are underestimated by 1 order of magnitude. In an annual balance, the most important mechanism for transport of methane into the atmosphere is through plants (61 %). This is followed by ebullition ( ∼ 35 %), while summertime molecular diffusion is negligible (0.02 %) compared to the diffusion through the snow during winter ( ∼ 4 %). We investigate the relationship between temporal changes in the CH4 fluxes, soil temperature, and soil moisture content. Our results highlight the heterogeneity in CH4 emissions at landscape scale and suggest that further improvements to the representation of large-scale hydrological conditions in the model will facilitate a more process-oriented land surface scheme and better simulate CH4 emissions under climate change. This is especially necessary at regional scales in Arctic ecosystems influenced by permafrost thaw.

Abstract We report the first observation of the $$\Xi _{c}(2930)^0$$ Ξc(2930)0 charmed-strange baryon with a significance greater than 5$$\sigma $$ σ . The $$\Xi _{c}(2930)^0$$ Ξc(2930)0 is found in its decay to $$K^- \Lambda _{c}^+$$ K-Λc+ in $$B^{-} \rightarrow K^{-} \Lambda _{c}^{+} \bar{\Lambda }_{c}^{-}$$ B-→K-Λc+Λ¯c- decays. The measured mass and width are $$[2928.9 \pm 3.0(\mathrm stat.)^{+0.9}_{-12.0}(\mathrm syst.)]$$ [2928.9±3.0(stat.)-12.0+0.9(syst.)] MeV/$$c^{2}$$ c2 and $$[19.5 \pm 8.4(\mathrm stat.) ^{+5.9}_{-7.9}(\mathrm syst.)]$$ [19.5±8.4(stat.)-7.9+5.9(syst.)] MeV, respectively, and the product branching fraction is $$\mathcal{B}(B^{-} \rightarrow \Xi _{c}(2930)^0 \bar{\Lambda }_{c}^{-}) \mathcal{B}(\Xi _{c}(2930)^0 \rightarrow K^- \Lambda _{c}^{+})=[1.73 \pm 0.45(\mathrm stat.) \pm 0.21(\mathrm syst.)]\times 10^{-4}$$ B(B-→Ξc(2930)0Λ¯c-)B(Ξc(2930)0→K-Λc+)=[1.73±0.45(stat.)±0.21(syst.)]×10-4 . We also measure $$\mathcal{B}(B^{-} \rightarrow K^{-} \Lambda _{c}^{+} \bar{\Lambda }_{c}^{-}) = [4.80 \pm 0.43(\mathrm stat.) \pm 0.60(\mathrm syst.)] \times 10^{-4}$$ B(B-→K-Λc+Λ¯c-)=[4.80±0.43(stat.)±0.60(syst.)]×10-4 with improved precision, and search for the charmonium-like state Y(4660) and its spin partner, $$Y_{\eta }$$ Yη , in the $$\Lambda _{c}^{+}\bar{\Lambda }_{c}^{-}$$ Λc+Λ¯c- invariant mass spectrum. No clear signals of the Y(4660) nor its spin partner are observed and the 90% credibility level (C.L.) upper limits on their production rates are determined. These measurements are obtained from a sample of $$(772\pm 11)\times 10^{6} B\bar{B}$$ (772±11)×106BB¯ pairs collected at the $$\Upsilon (4S)$$ Υ(4S) resonance by the Belle detector at the KEKB asymmetric energy electron–positron collider.

Recombinant adeno-associated virus (rAAV)-mediated gene delivery shows promise to transduce the pancreas, but safety/efficacy in a neoplastic context is not well established. To identify an ideal AAV serotype, route, and vector dose and assess safety, we have investigated the use of three AAV serotypes (6, 8, and 9) expressing GFP in a self-complementary (sc) AAV vector under an EF1α promoter (scAAV.GFP) following systemic or retrograde pancreatic intraductal delivery. Systemic delivery of scAAV9.GFP transduced the pancreas with high efficiency, but gene expression did not exceed >45% with the highest dose, 5 × 1012 viral genomes (vg). Intraductal delivery of 1 × 1011 vg scAAV6.GFP transduced acini, ductal cells, and islet cells with >50%, ∼48%, and >80% efficiency, respectively, and >80% pancreatic transduction was achieved with 5 × 1011 vg. In a KrasG12D-driven pancreatic cancer mouse model, intraductal delivery of scAAV6.GFP targeted acini, epithelial, and stromal cells and exhibited persistent gene expression 5 months post-delivery. In normal mice, intraductal delivery induced a transient increase in serum amylase/lipase that resolved within a day of infusion with no sustained pancreatic inflammation or fibrosis. Similarly, in PDAC mice, intraductal delivery did not increase pancreatic intraepithelial neoplasia progression/fibrosis. Our study demonstrates that scAAV6 targets the pancreas/neoplasm efficiently and safely via retrograde pancreatic intraductal delivery.

Osteoporosis is a disease characterized by low bone mass, most commonly caused by an increase in bone resorption that is not matched by sufficient bone formation. The most common complications of postmenopausal osteoporosis are bone-related defects and fractures. Fracture healing is a multifactorial bone regeneration process, influenced by both biological and mechanical factors related to age, osteoporosis and stability of the osteosynthesis. During the treatment of bone defects in osteoporotic conditions, imbalanced bone remodeling is the leading cause for implant failure. To overcome these problems, ethyl-2,5-dihydroxybenzoate (E-2,5-DHB), a drug that promotes bone formation and inhibits bone resorption, was used. E-2,5-DHB-incorporating titanium (Ti) implants using poly(lactic-co-glycolic acid) (PLGA) coating for local delivery of E-2,5-DHB were developed and the effects on bone healing of femoral defects were evaluated in an osteoporotic model. The release of E-2,5-DHB resulted in decreased bone resorption and increased bone formation around the implant. Thus, it was confirmed that, in the osteoporotic model, bone healing was increased and implant fixation was enhanced. These results suggested that E-2,5-DHB-coated Ti implants have great potential as an ultimate local drug delivery system for bone tissue scaffolds.

Summary: The mitogen-activated protein kinase (MAPK) pathway is a critical effector of oncogenic RAS signaling, and MAPK pathway inhibition may be an effective combination treatment strategy. We performed genome-scale loss-of-function CRISPR-Cas9 screens in the presence of a MEK1/2 inhibitor (MEKi) in KRAS-mutant pancreatic and lung cancer cell lines and identified genes that cooperate with MEK inhibition. While we observed heterogeneity in genetic modifiers of MEKi sensitivity across cell lines, several recurrent classes of synthetic lethal vulnerabilities emerged at the pathway level. Multiple members of receptor tyrosine kinase (RTK)-RAS-MAPK pathways scored as sensitizers to MEKi. In particular, we demonstrate that knockout, suppression, or degradation of SHOC2, a positive regulator of MAPK signaling, specifically cooperated with MEK inhibition to impair proliferation in RAS-driven cancer cells. The depletion of SHOC2 disrupted survival pathways triggered by feedback RTK signaling in response to MEK inhibition. Thus, these findings nominate SHOC2 as a potential target for combination therapy. : Sulahian, Kwon, and Walsh et al. performed several loss-of-function CRISPR-Cas9 screens in KRAS-mutant cancer cells treated with a MEK inhibitor and define the landscape of modifiers of MEK inhibitor sensitivity while highlighting that SHOC2 is a potent synthetic lethal target that serves as a critical signaling node to mediate MAP kinase pathway reactivation upon MEK inhibition. Keywords: Ras, KRAS, MEK inhibitor, synthetic lethal, SHOC2, CRISPR-Cas9 screen