The identification of effective tumor-suppressing neoantigens using a tumor-reactive TIL TCR-pMHC ternary complex.

Neoantigens are ideal targets for cancer immunotherapy because they are expressed de novo in tumor tissue but not in healthy tissue and are therefore recognized as foreign by the immune system. Advances in next-generation sequencing and bioinformatics technologies have enabled the quick identification and prediction of tumor-specific neoantigens; however, only a small fraction of predicted neoantigens are immunogenic. To improve the predictability of immunogenic neoantigens, we developed the in silico neoantigen prediction workflows VACINUSpMHC and VACINUSTCR: VACINUSpMHC incorporates physical binding between peptides and MHCs (pMHCs), and VACINUSTCR integrates T cell reactivity to the pMHC complex through deep learning-based pairing with T cell receptors (TCRs) of putative tumor-reactive CD8 tumor-infiltrating lymphocytes (TILs). We then validated our neoantigen prediction workflows both in vitro and in vivo in patients with hepatocellular carcinoma (HCC) and in a B16F10 mouse melanoma model. The predictive abilities of VACINUSpMHC and VACINUSTCR were confirmed in a validation cohort of 8 patients with HCC. Of a total of 118 neoantigen candidates predicted by VACINUSpMHC, 48 peptides were ultimately selected using VACINUSTCR. In vitro validation revealed that among the 48 predicted neoantigen candidates, 13 peptides were immunogenic. Assessment of the antitumor efficacy of the candidate neoepitopes using a VACINUSTCR in vivo mouse model suggested that vaccination with the predicted neoepitopes induced neoantigen-specific T cell responses and enabled the trafficking of neoantigen-specific CD8 + T cell clones into the tumor tissue, leading to tumor suppression. This study showed that the prediction of immunogenic neoantigens can be improved by integrating a tumor-reactive TIL TCR-pMHC ternary complex.

Unveiling a common phase transition pathway of high-density amorphous ices through time-resolved x-ray scattering.

Here, we investigate the hypothesis that despite the existence of at least two high-density amorphous ices, only one high-density liquid state exists in water. We prepared a very-high-density amorphous ice (VHDA) sample and rapidly increased its temperature to around 205 ± 10 K using laser-induced isochoric heating. This temperature falls within the so-called "no-man's land" well above the glass-liquid transition, wherein the IR laser pulse creates a metastable liquid state. Subsequently, this high-density liquid (HDL) state of water decompresses over time, and we examined the time-dependent structural changes using short x-ray pulses from a free electron laser. We observed a liquid-liquid transition to low-density liquid water (LDL) over time scales ranging from 20 ns to 3 µs, consistent with previous experimental results using expanded high-density amorphous ice (eHDA) as the initial state. In addition, the resulting LDL derived both from VHDA and eHDA displays similar density and degree of inhomogeneity. Our observation supports the idea that regardless of the initial annealing states of the high-density amorphous ices, the same HDL and final LDL states are reached at temperatures around 205 K.

Stroke walking and balance characteristics via principal component analysis.

Balance impairment is associated gait dysfunction with several quantitative spatiotemporal gait parameters in patients with stroke. However, the link between balance impairments and joint kinematics during walking remains unclear. Clinical assessments and gait measurements using motion analysis system was conducted in 44 stroke patients. This study utilised principal component analysis to identify key joint kinematics characteristics of patients with stroke during walking using average joint angles of pelvis and bilateral lower limbs in every gait-cycle percentile related to balance impairments. Reconstructed kinematics showed the differences in joint kinematics in both paretic and nonparetic lower limbs that can be distinguished by balance impairment, particularly in the sagittal planes during swing phase. The impaired balance group exhibited greater joint variability in both the paretic and nonparetic limbs in the sagittal plane during entire gait phase and during terminal swing phase respectively compared with those with high balance scores. This study provides a more comprehensive understanding of stroke hemiparesis gait patterns and suggests considering both nonparetic and paretic limb function, as well as bilateral coordination in clinical practice. Principal component analysis can be a useful assessment tool to distinguish differences in balance impairment and dynamic symmetry during gait in patients with stroke.

GnRH peripherally modulates nociceptor functions, exacerbating mechanical pain.

The function of peripheral nociceptors, the neurons that relay pain signals to the brain, are frequently tuned by local and systemic modulator substances. In this context, neurohormonal effects are emerging as an important modulatory mechanism, but many aspects remain to be elucidated. Here we report that gonadotropin-releasing hormone (GnRH), a brain-specific neurohormone, can aggravate pain by acting on nociceptors in mice. GnRH and GnRHR, the receptor for GnRH, are expressed in a nociceptor subpopulation. Administration of GnRH and its analogue, localized for selectively affecting the peripheral neurons, deteriorated mechanical pain, which was reproducible in neuropathic conditions. Nociceptor function was promoted by GnRH treatment in vitro, which appears to involve specific sensory transient receptor potential ion channels. These data suggest that peripheral GnRH can positively modulate nociceptor activities in its receptor-specific manner, contributing to pain exacerbation. Our study indicates that GnRH plays an important role in neurohormonal pain modulation via a peripheral mechanism.

Inverted nucleation for photoinduced nonequilibrium melting.

Ultrafast photoinduced melting provides an essential platform for studying nonequilibrium phase transitions by linking the kinetics of electron dynamics to ionic motions. Knowledge of dynamic balance in their energetics is essential to understanding how the ionic reaction is influenced by femtosecond photoexcited electrons with notable time lag depending on reaction mechanisms. Here, by directly imaging fluctuating density distributions and evaluating the ionic pressure and Gibbs free energy from two-temperature molecular dynamics that verified experimental results, we uncovered that transient ionic pressure, triggered by photoexcited electrons, controls the overall melting kinetics. In particular, ultrafast nonequilibrium melting can be described by the reverse nucleation process with voids as nucleation seeds. The strongly driven solid-to-liquid transition of metallic gold is successfully explained by void nucleation facilitated by photoexcited electron-initiated ionic pressure, establishing a solid knowledge base for understanding ultrafast nonequilibrium kinetics.

Orbital-selective time-domain signature of nematicity dynamics in the charge-density-wave phase of La1.65Eu0.2Sr0.15CuO4.

Understanding the interplay between charge, nematic, and structural ordering tendencies in cuprate superconductors is critical to unraveling their complex phase diagram. Using pump-probe time-resolved resonant X-ray scattering on the (0 0 1) Bragg peak at the Cu [Formula: see text] and O [Formula: see text] resonances, we investigate nonequilibrium dynamics of [Formula: see text] nematic order and its association with both charge density wave (CDW) order and lattice dynamics in La[Formula: see text]Eu[Formula: see text]Sr[Formula: see text]CuO[Formula: see text]. The orbital selectivity of the resonant X-ray scattering cross-section allows nematicity dynamics associated with the planar O 2[Formula: see text] and Cu 3[Formula: see text] states to be distinguished from the response of anisotropic lattice distortions. A direct time-domain comparison of CDW translational-symmetry breaking and nematic rotational-symmetry breaking reveals that these broken symmetries remain closely linked in the photoexcited state, consistent with the stability of CDW topological defects in the investigated pump fluence regime.

Ertugliflozin for Functional Mitral Regurgitation Associated With Heart Failure: EFFORT Trial.

BACKGROUND: The morbidity and mortality rates of patients with heart failure (HF) and functional mitral regurgitation (MR) remain substantial despite guideline-directed medical therapy for HF. We evaluated the efficacy of ertugliflozin for reduction of functional MR associated with HF with mild to moderately reduced ejection fraction. METHODS: The EFFORT trial (Ertugliflozin for Functional Mitral Regurgitation) was a multicenter, double-blind, randomized trial to examine the hypothesis that the sodium-glucose cotransporter 2 inhibitor ertugliflozin is effective for improving MR in patients with HF with New York Heart Association functional class II or III, 35%≤ejection fraction<50%, and effective regurgitant orifice area of chronic functional MR >0.1 cm2 on baseline echocardiography. We randomly assigned 128 patients to receive either ertugliflozin or placebo in addition to guideline-directed medical therapy for HF. The primary end point was change in effective regurgitant orifice area of functional MR from baseline to the 12-month follow-up. Secondary end points included changes in regurgitant volume, left ventricular (LV) volume indices, left atrial volume index, LV global longitudinal strain, and NT-proBNP (N-terminal pro-B-type natriuretic peptide). RESULTS: The treatment groups were generally well-balanced with regard to baseline characteristics: mean age, 66±11 years; 61% men; 13% diabetes; 51% atrial fibrillation; 43% use of angiotensin receptor-neprilysin inhibitor; ejection fraction, 42±8%; and effective regurgitant orifice area, 0.20±0.12 cm2. The decrease in effective regurgitant orifice area was significantly greater in the ertugliflozin group than in the placebo group (-0.05±0.06 versus 0.03±0.12 cm2; P<0.001). Compared with placebo, ertugliflozin significantly reduced regurgitant volume by 11.2 mL (95% CI, -16.1 to -6.3; P=0.009), left atrial volume index by 6.0 mL/m2 (95% CI, -12.16 to 0.15; P=0.005), and LV global longitudinal strain by 1.44% (95% CI, -2.42% to -0.46%; P=0.004). There were no significant between-group differences regarding changes in LV volume indices, ejection fraction, or NT-proBNP levels. Serious adverse events occurred in one patient (1.6%) in the ertugliflozin group and 6 (9.2%) in the placebo group (P=0.12). CONCLUSIONS: Among patients with functional MR associated with HF, ertugliflozin significantly improved LV global longitudinal strain and left atrial remodeling, and reduced functional MR. Sodium-glucose cotransporter 2 inhibitors may be considered for patients with functional MR. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04231331.

An Ultrasoft and Flexible PDMS-Based Balloon-Type Implantable Device for Controlled Drug Delivery.

Non-biodegradable implants have undergone extensive investigation as drug delivery devices to enable advanced healthcare toward personalized medicine. However, fibroblast encapsulation is one of the major challenges in all non-biodegradable implants, besides other challenges such as high initial burst, risk of membrane rupture, high onset time, non-conformal contact with tissues, and tissue damage. To tackle such challenges, we propose a novel ultrasoft and flexible balloon-type drug delivery device for unidirectional and long-term controlled release. The ultrasoft balloon-type device (USBD) was fabricated by using selective bonding between 2 polydimethylsiloxane (PDMS) membranes and injecting a fluid into the non-bonded area between them. The balloon acted as a reservoir containing a liquid drug, and at the same time, the membrane of the balloon itself acted as the pathway for release based on diffusion. The release was modulated by tuning the thickness and composition of the PDMS membrane. Regardless of the thickness and composition, all devices exhibited zero-order release behavior. The longest zero-order release and nearly zero-order release were achieved for 30 days and 58 days at a release rate of 1.16 µg/day and 1.68 µg/day, respectively. In vivo evaluation was performed for 35 days in living rats, where the USBD maintained zero-order and nearly zero-order release for 28 days and 35 days, respectively. Thanks to the employment of ultrasoft and flexible membranes and device design, the USBD could achieve minimal tissue damage and foreign body responses. It is expected that the proposed device may provide a novel approach for long-term drug delivery with new therapeutic modalities.

Impact of rumen cannulation surgery on rumen microbiota composition in Hanwoo steers.

Rumen cannulation is a surgical technique used to collect rumen contents from ruminants. However, rumen cannulation surgery may potentially impact the composition of the rumen microbiota. This study aimed to examine the longitudinal alterations in the rumen microbiota composition of Hanwoo steers after cannulation surgery. In this study, eight Hanwoo steers were used; four steers underwent rumen cannulation surgery (cannulation group), while the remaining four were left intact (control group). Rumen samples were collected from all eight steers using the stomach tubing method on the day before surgery (day 0) and on postoperative days 1, 4, 7, 10, 14, 17, 21, 24, and 28, resulting in 80 samples (10 timepoints × 8 animals). The microbiota of all 80 samples were analyzed using 16S rRNA gene amplicon sequencing with Quantitative Insights into Microbial Ecology version 2 (QIIME2). There were no significant differences (p > 0.05) in all major phyla and most major genera representing at least 0.5% of total sequences across all 80 samples between the control and cannulation groups on the preoperative and postoperative days. However, while the alpha diversity indices did not differ (p > 0.05) between the two groups on the preoperative day, they significantly differed (p < 0.05) between the two groups on the postoperative days. Further, the overall microbial distribution based on both unweighted and weighted principal coordinate analysis plots significantly differed (p < 0.05) between the two groups on both the preoperative and postoperative days. Orthogonal polynomial contrasts indicated that major genera and microbial diversity in the cannulation group decreased following surgery but returned to their initial states by postoperative day 28. In conclusion, this study demonstrates that rumen cannulation surgery affects some major taxa and microbial diversity, suggesting that the rumen cannulation method can alter the composition of rumen microbiota in Hanwoo steers.

Using Surface-Enhanced Raman Spectroscopy to Probe Surface-Localized Nonthermal Plasma Activation.

Low-temperature, nonthermal plasmas generate a complex environment even when operated in nonreactive gases. Plasma-produced species impinge on exposed surfaces, and their thermalization is highly localized at the surface. Here we present a Raman thermometry approach to quantifying the resulting degree of surface heating. A nanostructured silver substrate is used to enhance the Raman signal and make it easily distinguishable from the background radiation from the plasma. Phenyl phosphonic acid is used as a molecular probe. Even under moderate plasma power and density, we measure a significant degree of vibrational excitation for the phenyl group, corresponding to an increase in surface temperature of ∼80 °C at a plasma density of 2 × 1010 cm-3. This work confirms that surface-localized thermal effects can be quantified in low-temperature plasma processes. Their characterization is needed to improve our understanding of the plasma-induced activation of surface reactions, which is highly relevant for a broad range of plasma-driven processes.

Association between sickness presenteeism and depressive symptoms: a cross-sectional study using the 6th Korean working conditions survey.

PURPOSE: This study aimed to reveal the relationship of the days of experiencing sickness presentism and depressive symptoms among Korean workers. Sickness presenteeism which defined as the act of going to work despite being feeling unhealthy triggers various adverse effects on mental health, including increased risks of depression. Furthermore, Sickness presenteeism is a major social issue causing substantial socioeconomic costs. METHODS: The data of 25120 participants from sixth Korean Working Condition Survey was utilized in this cross-sectional study. Sickness presenteeism was defined using a self-reported questionnaire and depressive symptoms were assessed by WHO well-being index. Multivariate logistic regression analysis was conducted to calculate the odd ratios for depressive symptoms regarding the number of days experiencing sickness presenteeism. We calculated odds ratios (ORs) and 95% confidence interval (95% CI) for depressive symptoms after categorizing participants into three groups based on the duration of experiencing sickness presenteeism, using cut-off values of 3 and 5 days. RESULTS: Workers who have experienced sickness presenteeism for more than 5 days were at highest risk for depressive symptoms than referent group (OR 2.87; 95% CI 2.17-3.76 in male, OR 3.86; 95% CI 3.02-4.91 in female). Furthermore, there was a trend of increasing risk for depressive symptom as the duration of experiencing sickness presenteeism extended. CONCLUSION: This study presents the association between experiencing sickness presenteeism in the previous 12 months and depressive symptoms. Based on the results, we provide individual and organizational strategies of reducing sickness presenteeism. Also, screening for workers who have experienced sickness presenteeism are needed to ensure good mental health.

Sinus floor augmentation using mineralized freeze-dried bone allograft combined with recombinant human bone morphogenetic protein-2 (rhBMP-2): A long-term retrospective study.

Background/purpose: The combination of recombinant human bone morphogenetic protein-2 (rhBMP-2) with a carrier material has not been extensively studied. This study aimed to evaluate the clinical, radiological, and histomorphometric outcomes of sinus floor augmentation using a 3:7 mixture of cancellous and cortical freeze-dried bone allografts (mixed AG) combined with rhBMP-2. Materials and methods: Mixed AG was used for sinus floor augmentation in a total of 21 patients with a residual alveolar bone height <5 mm. Among the total 47 sites, augmentation with and without rhBMP-2 was performed in 26 and 21 sites, respectively. Radiographic parameters were assessed using cone-beam computed tomography. After a six-month healing period, core biopsies were harvested for histomorphometric analysis. Results: The bone gain after healing was 13.36 ± 3.9 mm and 12.07 ± 3.8 mm in the mixed AG alone and mixed AG with rhBMP-2 groups, respectively. The survival rate of implants in both groups was 100% during the follow-up period. The proportion of newly formed bone was 24.6 ± 10.2% and 39.7 ± 18.3% in the mixed AG alone and mixed AG with rhBMP-2 groups, respectively (P < 0.05). Moreover, the percentage of residual graft material was 21.0 ± 12.2% and 9.6 ± 10.0% in the mixed AG alone and mixed AG with rhBMP-2 groups, respectively (P < 0.05). Conclusion: Mixed AG combined with rhBMP-2 could be a suitable material for sinus floor augmentation. This combination may reduce the treatment time and improve the predictability of implant placement.

Nickel-Catalyzed Hydrofluorination in Unactivated Alkenes: Regio- and Enantioselective C-F Bond Formation.

Catalytic formation of a regio- and enantioselective C-F bond chiral center from readily available alkenes is a crucial goal, yet it continues to pose significant challenges in organic synthesis. Here, we report the regioselective formation of C-F bonds facilitated by NiH catalysis and a coordination directing strategy that enables precise hydrofluorination of both terminal and internal alkenes. Notably, we have optimized this methodology to achieve high enantioselectivity in creating aliphatic C-F stereogenic centers especially with ß,γ-alkenyl substrates, using a tailored chiral Bn-BOx ligand. Another pivotal finding in our research is the identification of the (+)-nonlinear effect under optimized conditions, allowing for high enantioselectivity even with moderately enantiomerically enriched chiral ligands. Given the significant role of fluorine in pharmaceuticals and synthetic materials, this research offers essential insights into the regioselective and enantioselective formation of C-F bond chiral centers, paving the way for the efficient production of valuable fluorinated compounds.

Dynamic three-dimensional structures of a metal-organic framework captured with femtosecond serial crystallography.

Crystalline systems consisting of small-molecule building blocks have emerged as promising materials with diverse applications. It is of great importance to characterize not only their static structures but also the conversion of their structures in response to external stimuli. Femtosecond time-resolved crystallography has the potential to probe the real-time dynamics of structural transitions, but, thus far, this has not been realized for chemical reactions in non-biological crystals. In this study, we applied time-resolved serial femtosecond crystallography (TR-SFX), a powerful technique for visualizing protein structural dynamics, to a metal-organic framework, consisting of Fe porphyrins and hexazirconium nodes, and elucidated its structural dynamics. The time-resolved electron density maps derived from the TR-SFX data unveil trifurcating structural pathways: coherent oscillatory movements of Zr and Fe atoms, a transient structure with the Fe porphyrins and Zr6 nodes undergoing doming and disordering movements, respectively, and a vibrationally hot structure with isotropic structural disorder. These findings demonstrate the feasibility of using TR-SFX to study chemical systems.

Validity and reliability of the self-care behaviour scale for patients with left ventricular assist device.

AIMS: To evaluate the validity and reliability of the self-care behaviour scale for patients with left ventricular assist devices. DESIGN: Methodological study. METHODS: The English version of the scale was translated into Korean, and it was then back-translated into English. Survey data were collected from 32 patients with left ventricular assist device in South Korea, and construct validity, content validity and reliability were analysed. RESULTS: The original self-care behaviour scale comprises three domains and 33 items, whereas the Korean self-care behaviour scale comprises 27 items and five domains: device management, wound management, symptom monitoring, activated healthcare system and self-care management. Cronbach's alpha for the overall scale was 0.94, and that for the five domains ranged from 0.36 to 0.90. The intraclass correlation coefficient for the overall scale was 0.89, and the five domains ranged from 0.71 to 0.88. CONCLUSION: The newly evaluated scale would be valid and reliable in measure self-care behaviour for patients with a left ventricular assist device. IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: Patients can manage the left ventricular assist device on their own based on evidence and use it as a tool for effective communication with medical professionals.

Simultaneous generation and manipulation of terahertz waves based on nonlinear leaky-waveguide antennas with integrated bianisotropic metasurfaces.

We hereby propose and theoretically investigate a new scheme for simultaneous generation and manipulation of terahertz (THz) waves through difference frequency generation facilitated by a metasurface-assisted nonlinear leaky waveguide antenna. The proposed structure integrates a nonlinear optical waveguide, composed of multiple AlxGa1-xAs layers, with a THz leaky waveguide, wherein a bianisotropic metasurface realizes the radiating aperture. By explicitly utilizing the electric, magnetic, and magnetoelectric coupling responses of the metasurface, we demonstrate that the generated THz wave can be induced as a tightly confined, phase-matched guided mode for efficient generation of the THz wave. Additionally, this approach allows the THz wave to be transformed into a directive beam, radiating at a user-defined leakage rate and direction. Our numerical analyses suggest that THz beams ranging from 2.85 THz to 3.05 THz can be steered from 4 ∘ to 40 ∘, utilizing the inherent beam-steering capabilities of the leaky-waveguide antenna. Within this THz frequency spectrum, the phase matching condition is achieved by adjusting the optical wavelengths between 1.6µm and 1.52µm. In particular, the nonlinear conversion efficiency is 2.9 × 10-5 [1/W] at 3 THz.

Association between temporary employment and current smoking and change in smoking behaviors: A prospective cohort study from South Korea (2009-2018).

Background Previous studies have suggested that employment insecurity is associated with adverse health outcomes. We explored the association between temporary employment and smoking behaviors.Methods We analyzed 11,795 workers (51,867 observations) from the Korea Health Panel Study (2009-2018). Employment types were categorized as regular, fixed-term, or daily, based on the duration of labor contract. The outcomes were current smoking status and changes in smoking behavior (initiation or cessation) in the following year. Generalized estimating equations were used to estimate odds ratio (OR) and 95% confidence interval (CI).Results The proportions of fixed-term and daily workers were 41.2% and 16.4% for women and 23.6% and 12.4% for men, respectively. Temporary employment was associated with increased odds of current smoking, while also demonstrating prospective associations with changes in smoking behaviors. For instance, in prospective analyses, male workers with fixed-term and daily employments were associated with a decreased likelihood of smoking cessation (OR:0.77; 95% CI:0.65-0.91 for fixed-term employment and OR:0.66; 95% CI:0.52-0.83 for daily employment) in the following year compared to those with regular employment. Moreover, those experiencing consecutive temporary employment was most inversely associated with smoking cessation in both men (OR:0.56; 95% CI:0.44-0.71) and women (OR:0.37; 95% CI:0.16-0.85) compared to those experiencing consecutive regular employment. However, no clear association between temporary employment and smoking initiation was observed in both men and women.Conclusions Temporary employment is directly associated with current smoking and inversely associated with smoking cessation. Policies are needed to improve job insecurity among temporary employees.