Transcriptome analysis of cynomolgus macaques throughout their lifespan reveals age-related immune patterns.

Despite the different perspectives by diverse research sectors spanning several decades, aging research remains uncharted territory for human beings. Therefore, we investigated the transcriptomic characteristics of eight male healthy cynomolgus macaques, and the annual sampling was designed with two individuals in four age groups. As a laboratory animal, the macaques were meticulously shielded from all environmental factors except aging. The results showed recent findings of certain immune response and the age-associated network of primate immunity. Three important aging patterns were identified and each gene clusters represented a different immune response. The increased expression pattern was predominantly associated with innate immune cells, such as Neutrophils and NK cells, causing chronic inflammation with aging whereas the other two decreased patterns were associated with adaptive immunity, especially "B cell activation" affecting antibody diversity of aging. Furthermore, the hub gene network of the patterns reflected transcriptomic age and correlated with human illness status, aiding in future human disease prediction. Our macaque transcriptome profiling results offer systematic insights into the age-related immunological features of primates.

Weld Zone Analysis Based on FCAW Mechanical Characteristics and Heat Transfer Analysis of 316L Stainless Steel for Liquefied Hydrogen Tanks.

The International Maritime Organization (IMO) is currently rolling out more restrictive regulations in order to achieve net-zero GHG emissions by 2050. In response, the shipping industry is planning to pivot to green energy sources such as hydrogen fuel. However, since hydrogen has an extremely low boiling point (-253 °C), materials for storing liquid hydrogen must be highly resistant to low-temperature brittleness and hydrogen embrittlement. A 316L stainless steel is a typical material that meets these requirements, and various welds have been studied. In this study, 3 pass butt welding was performed by applying the FCAW (flux cored arc welding) process to 10 mm thick ASTM-A240M-316L stainless steel, with the size of the fusion zone and HAZ investigated by mechanical testing and heat transfer FE analysis according to process variables, such as heat input, welding speed, and the number of passes. In all cases, the yield and tensile strengths were about 10% and 3% higher than the base metal, respectively. Furthermore, heat transfer FE analysis showed an average error rate of 1.3% for penetration and 10.5% for width and confirmed the size of the HAZ, which experienced temperatures between 500 °C and 800 °C.

Efficacy and Safety of Alogliptin-Pioglitazone Combination for Type 2 Diabetes Mellitus Poorly Controlled with Metformin: A Multicenter, Double-Blind Randomized Trial.

Background: Guidelines for switching to triple combination therapy directly after monotherapy failure are limited. This study investigated the efficacy, long-term sustainability, and safety of either mono or dual add-on therapy using alogliptin and pioglitazone for patients with type 2 diabetes mellitus (T2DM) who did not achieve their target glycemic range with metformin monotherapy. Methods: The Practical Evidence of Antidiabetic Combination Therapy in Korea (PEAK) was a multicenter, placebo-controlled, double-blind, randomized trial. A total of 214 participants were randomized to receive alogliptin+pioglitazone (Alo+Pio group, n=70), alogliptin (Alo group, n=75), or pioglitazone (Pio group, n=69). The primary outcome was the difference in glycosylated hemoglobin (HbA1c) levels between the three groups at baseline to 24 weeks. For durability, the achievement of HbA1c levels <7% and <6.5% was compared in each group. The number of adverse events was investigated for safety. Results: After 24 weeks of treatment, the change of HbA1c in the Alo+Pio, Alo, and Pio groups were -1.38%±0.08%, -1.03%±0.08%, and -0.84%±0.08%, respectively. The Alo+Pio group had significantly lower HbA1c levels than the other groups (P=0.0063, P<0.0001) and had a higher proportion of patients with target HbA1c achievement. In addition, insulin sensitivity and ß-cell function, lipid profiles, and other metabolic indicators were also improved. There were no significant safety issues in patients treated with triple combination therapy. Conclusion: Early combination triple therapy showed better efficacy and durability than the single add-on (dual) therapy. Therefore, combination therapy with metformin, alogliptin, and pioglitazone is a valuable early treatment option for T2DM poorly controlled with metformin monotherapy.

Utilization of nicking properties of CRISPR-Cas12a effector for genome editing.

The CRISPR-Cas nickase system for genome editing has attracted considerable attention owing to its safety, efficiency, and versatility. Although alternative effectors to Cas9 have the potential to expand the scope of genome editing, their application has not been optimized. Herein, we used an enhanced CRISPR-Cas12a nickase system to induce mutations by targeting genes in a human-derived cell line. The optimized CRISPR-Cas12a nickase system effectively introduced mutations into target genes under a specific directionality and distance between nickases. In particular, the single-mode Cas12a nickase system can induce the target-specific mutations with less DNA double-strand breaks. By inducing mutations in the Thymine-rich target genes in single- or dual-mode, Cas12a nickase compensates the limitations of Cas9 nickase and is expected to contribute to the development of future genome editing technologies.

A fluorescent probe for selective detection of lysosomal ß-hexosaminidase in live cells.

Determining the activity of lysosomal ß-hexosaminidase in cells is of great importance for understanding the roles that these enzymes play in pathophysiological events. Herein, we designed the new fluorescent probe, ßGalNAc-Rhod-CM(NEt2), which consisted of a ßGalNAc-linked rhodol unit serving as a ß-hexosaminidase reactive fluorogenic moiety and a N,N'-diethylaminocoumarin (CM(NEt2)) group acting as a fluorescence marker for determining the degree of cell permeabilization. Treatment of ßGalNAc-Rhod-CM(NEt2) with ß-hexosaminidase promoted generation of Rhod-CM(NEt2), thereby leading to an increase in the intensity of fluorescence of Rhod. However, this probe did not respond to the functionally related glycosidase, O-GlcNAcase. The detection limit of ßGalNAc-Rhod-CM(NEt2) for ß-hexosaminidase was determined to be 0.52 nM, indicating that it has high sensitivity for this enzyme. Furthermore, the probe functioned as an excellent fluorogenic substrate for ß-hexosaminidase with kcat and Km values of 17 sec-1 and 22 µM, respectively. The results of cell studies using ßGalNAc-Rhod-CM(NEt2) showed that levels of ß-hexosaminidase activity in cells can be determined by measuring the intensity of fluorescence arising from Rhod and that the intensity of fluorescence of CM(NEt2) can be employed to determine the degree of cell permeabilization of the probe. Utilizing the new probe, we assessed ß-hexosaminidase activities in several types of cells and evaluated the effect of glucose concentrations in culture media on the activity of this enzyme.

An Improved Method for Deriving the Heat Source Model for FCAW of 9% Nickel Steel for Cryogenic Tanks.

The International Maritime Organization (IMO) is tightening regulations on air pollutants. Consequently, more LNG-powered ships are being used to adhere to the sulfur oxide regulations. Among the tank materials for storing LNG, 9% nickel steel is widely used for cryogenic tanks and containers due to its high cryogenic impact toughness and high yield strength. Hence, numerous studies have sought to predict 9% nickel steel welding distortion. Previously, a methodology to derive the optimal parameters constituting the Goldak welding heat source for arc welding was developed. This was achieved by integrating heat transfer finite element analysis and optimization algorithms. However, this process is time-consuming, and the resulting shape of the weld differs by ~15% from its actual size. Therefore, this study proposes a simplified model to reduce the analysis time required for the arc welding process. Moreover, a new objective function and temperature constraints are presented to derive a more sophisticated heat source model for arc welding. As a result, the analysis time was reduced by ~70% compared to that previously reported, and the error rates of the weld geometry and HAZ size were within 10% and 15% of the actual weld, respectively. The findings of this study provide a strategy to rapidly predict welding distortion in the field, which can inform the revision of welding guidelines and overall welded structure designs.

Demonstration of programmable light intensity of a micro-LED with a Hf-based ferroelectric ITZO TFT for Mura-free displays.

We demonstrate the programmable light intensity of a micro-LED by compensating threshold voltage variability of thin-film transistors (TFTs) by introducing a non-volatile programmable ferroelectric material, HfZrO2 (HZO) into the gate stack of the TFT. We fabricated an amorphous ITZO TFT, ferroelectric TFTs (FeTFTs), and micro-LEDs and verified the feasibility of our proposed current-driving active matrix circuit. Importantly, we successfully present the programmed multi-level lighting of the micro-LED, utilizing partial polarization switching in the a-ITZO FeTFT. We expect that this approach will be highly promising for the next-generation display technology, replacing complicated threshold voltage compensation circuits with a simple a-ITZO FeTFT.

A fluorescent probe to simultaneously detect both O-GlcNAcase and phosphatase.

O-GlcNAc modification of proteins often has crosstalk with protein phosphorylation. These posttranslational modifications are highly dynamic events that modulate a wide range of cellular processes. Owing to the physiological and pathological significance of protein O-GlcNAcylation and phosphorylation, we designed the fluorescent probe, ßGlcNAc-CM-Rhod-P, to differentially detect activities of O-GlcNAcase (OGA) and phosphatase, enzymes that are responsible for these modifications. ßGlcNAc-CM-Rhod-P was comprised of a ßGlcNAc-conjugated coumarin (ßGlcNAc-CM) acting as an OGA substrate, a phosphorylated rhodol (Rhod-P) as a phosphatase substrate and a piperazine bridge. Because the emission wavelength maxima of CM and Rhod liberated from the probe are greatly different (100 nm), spectral interference is avoided. The results of this study revealed that treatment of ßGlcNAc-CM-Rhod-P with OGA promotes formation of the GlcNAc-cleaved probe, CM-Rhod-P, and a consequent increase in the intensity of fluorescence associated with free CM. Also, it was found that exposure of the probe to phosphatase produces a dephosphorylated probe, ßGlcNAc-CM-Rhod, which displays strong fluorescence arising from free Rhod. On the other hand, when incubated with both OGA and phosphatase, ßGlcNAc-CM-Rhod-P was converted to CM-Rhod which lacked both ßGlcNAc and phosphoryl groups, in conjunction with increases in the intensities of fluorescence arising from both free CM and Rhod. This probe was employed to detect activities of OGA and phosphatase in cell lysates and to fluorescently image both enzymes in cells. Collectively, the findings indicate that ßGlcNAc-CM-Rhod-P can be utilized as a chemical tool to simultaneously determine activities of OGA and phosphatase.

Study on the Global Sustainability of the Korean Construction Industry Based on the GRI Standards.

This study began with the increasing importance of ESG through sustainable management evaluation across all industries, predicting market demand through the ESG management paradigm and financial environment changes in the global industry, and establishing international strategies for the construction industry. Compared to other industries, the construction industry is in the early stages of ESG formation, and it is unclear how to expand its base by establishing evaluation system standards such as innovation of individual services, interaction of social capital, and definition of stakeholders. Currently, some large construction companies in the construction industry are publishing sustainability management reports at the group level, but given the recently strengthened global sustainability of ESG by GRI Standards, efficient analysis of global construction markets and strategic orders are needed. Therefore, this study focuses on assessing the sustainability strategies and directions of the construction industry from an ESG perspective. To this end, sustainability issues and insights, as well as global issues in Korea and the worldwide construction sector, were analyzed. The analysis showed that global construction companies were highly interested in business management approaches, such as safety and health, as critical issues regarding the construction industry's sustainability strategy. In contrast, South Korean construction companies prioritize business values such as value creation, fair trade, and win-win. Both global and South Korean construction companies have been working on greenhouse gas reduction and energy sustainability. Regarding other issues, cultivating construction specialists, enhancing the job training system, and limiting serious accidents and safety mishaps were all significant from a social standpoint among South Korean construction companies. Conversely, global construction companies appeared to focus on issues related to ethical and environmental management from an organizational standpoint.

The extent of harmful volatile organic compounds released when smoking after breaking the flavor capsules of heat-not-burn (HNB) cigarette products.

A number of flavored capsule heat-not-burn (FC-HNB) tobacco products such as IQOS, Lil, and Glo have been introduced as a new generation of cigarettes. As they can release various types of volatile organic compounds (VOCs), it is important to assess the harmfulness associated with their use. Thus, the composition of VOCs in HNB cigarette vapor was evaluated to investigate the interactive roles of key variables controlling the relationships between VOC composition and capsule breaking, particularly the compositional changes induced by capsule breaking and release of flavor from FC-HNB cigarettes relative to regular products. As the capsules of FC-HNB cigarettes were broken, the total VOC concentrations increased by as high as eight times from 60.3 ± 0.48 to 488 ± 21.8 µg cig-1. The key VOC components released after breaking the flavored capsules were identified as ethyl butyrate (157 ± 13.6 µg cig-1; Lil), isoamyl acetate (76.9 ± 1.98 µg cig-1; Lil), and limonene (52.3 ± 3.29 µg cig-1; Glo). If the primary health risks of FC-HNB cigarette vapor are assessed using National Institute for Occupational Safety & Health (NIOSH) guidelines, 2,3-butanedinone exceeds the maximum daily intake limit (i.e., 0.05 mg day-1). Our study is expected to offer valuable insights into the harmful effects of direct and indirect exposure to various VOCs in FC-HNB products.

An Indoor-Monitoring LiDAR Sensor for Patients with Alzheimer Disease Residing in Long-Term Care Facilities.

This paper introduces an indoor-monitoring LiDAR sensor for patients with Alzheimer disease residing in long-term care facilities (LTCFs), and this sensor exploits an optoelectronic analog front-end (AFE) to detect light signals from targets by utilizing on-chip avalanche photodiodes (APDs) realized in a 180 nm CMOS process and a neural processing unit (NPU) used for motion detection and decisions, especially for incidents of falls occurring in LTCFs. The AFE consists of an on-chip CMOS P+/N-well APD, a linear-mode transimpedance amplifier, a post-amplifier, and a time-to-digital converter, whereas the NPU exploits network sparsity and approximate processing elements for low-power operation. This work provides a potential solution of low-cost, low-power, indoor-monitoring LiDAR sensors for patients with Alzheimer disease in LTCFs.

Hyaluronidase 6 Does Not Affect Cumulus-Oocyte Complex Dispersal and Male Mice Fertility.

Glycosylphosphatidylinositol-anchored sperm hyaluronidases (HYAL) assist sperm penetration through the cumulus-oocyte complex (COC), but their role in mammalian fertilization remains unclear. Previously, we demonstrated that sperm from HYAL 5 and 7 double-knockout (dKO) mice produced significantly less offspring than sperm from wild-type mice due to defective COC dispersal. However, the HYAL6 gene remained active in the sperm from the dKO mice, indicating that they were not entirely infertile. This study explored the role of HYAL6 in fertilization by analyzing HYAL6-mutant mice. In this mouse model, HYAL5 and HYAL7 were present in the HYAL6-knockout sperm, and they could disperse hyaluronic acid. We found that HYAL6 was present on the surface of sperm. However, male mice lacking the HYAL6 gene had normal fertility, testicular integrity, and sperm characteristics. Furthermore, in vitro fertilization assays demonstrated that HYAL6-deficient epididymal sperm functioned normally. Therefore, HYAL6 is dispensable for fertilization.

Highly specific chimeric DNA-RNA-guided genome editing with enhanced CRISPR-Cas12a system.

The clustered regularly interspaced short palindromic repeats (CRISPR)-Cas12a system is composed of a Cas12a effector that acts as a DNA-cleaving endonuclease and a crispr RNA (crRNA) that guides the effector to the target DNA. It is considered a key molecule for inducing target-specific gene editing in various living systems. Here, we improved the efficiency and specificity of the CRISPR-Cas12a system through protein and crRNA engineering. In particular, to optimize the CRISPR-Cas12a system at the molecular level, we used a chimeric DNA-RNA guide chemically similar to crRNA to maximize target sequence specificity. Compared with the wild-type (wt)-Cas12a system, when using enhanced Cas12a system (en-Cas12a), the efficiency and target specificity improved on average by 2.58 and 2.77 times, respectively. In our study, when the chimeric DNA-RNA-guided en-Cas12a effector was used, the gene-editing efficiency and accuracy were simultaneously increased. These findings could contribute to highly accurate genome editing, such as human gene therapy, in the near future.

Expansion of the prime editing modality with Cas9 from Francisella novicida.

Prime editing can induce a desired base substitution, insertion, or deletion in a target gene using reverse transcriptase after nick formation by CRISPR nickase. In this study, we develop a technology that can be used to insert or replace external bases in the target DNA sequence by linking reverse transcriptase to the Francisella novicida Cas9, which is a CRISPR-Cas9 ortholog. Using FnCas9(H969A) nickase, the targeting limitation of existing Streptococcus pyogenes Cas9 nickase [SpCas9(H840A)]-based prime editing is dramatically extended, and accurate prime editing is induced specifically for the target genes in human cell lines.

Sperm hyaluronidase is critical to mammals' fertilization for its ability to disperse cumulus-oocyte complex layer.

Glycosylphosphatidylinositol-anchored sperm hyaluronidases have long been believed to assist in sperm penetration through the cumulus-oocyte complex (COC); however, their role in mammalian fertilization remains unclear. Previously, we have shown that hyaluronidase 5 (Hyal5)/Hyal7 double-knockout (dKO) mice produce significantly fewer offspring than their wild-type (WT) counterparts because of defective COC dispersal. Male infertility is mainly caused by a low sperm count. It can be further exacerbated by the deficiency of sperm hyaluronidase, which disperses the cumulus cells of the outer layer of the COC. In the current study, we evaluated the effects of a low count of Hyal-deficient sperm and conditions of ovulated oocytes on the fertilization rate using a mouse model. Our results demonstrated that a low sperm count further decreases the in vitro fertilization (IVF) rate of Hyal-deficient dKO spermatozoa. In addition, the dKO spermatozoa resulted in a fertilization rate of 12.5% upon fertilizing COCs with a thick cumulus layer, whereas the IVF rate was comparable to that of WT spermatozoa when oocytes with a thin or no cumulus layer were fertilized. Finally, we proved that the IVF rate of dKO spermatozoa could be recovered by adding rat spermatozoa as a source of sperm hyal. Our results suggest that a deficiency of proteins involved in fertilization, such as sperm hyal, has a vital role in fertilization.

Alzheimer's vulnerable brain region relies on a distinct retromer core dedicated to endosomal recycling.

Whether and how the pathogenic disruptions in endosomal trafficking observed in Alzheimer's disease (AD) are linked to its anatomical vulnerability remain unknown. Here, we began addressing these questions by showing that neurons are enriched with a second retromer core, organized around VPS26b, differentially dedicated to endosomal recycling. Next, by imaging mouse models, we show that the trans-entorhinal cortex, a region most vulnerable to AD, is most susceptible to VPS26b depletion-a finding validated by electrophysiology, immunocytochemistry, and behavior. VPS26b was then found enriched in the trans-entorhinal cortex of human brains, where both VPS26b and the retromer-related receptor SORL1 were found deficient in AD. Finally, by regulating glutamate receptor and SORL1 recycling, we show that VPS26b can mediate regionally selective synaptic dysfunction and SORL1 deficiency. Together with the trans-entorhinal's unique network properties, hypothesized to impose a heavy demand on endosomal recycling, these results suggest a general mechanism that can explain AD's regional vulnerability.

A Study to Derive Equivalent Mechanical Properties of Porous Materials with Orthotropic Elasticity.

The need for diverse materials has emerged as industry becomes more developed, and there is a need for materials with pores in various industries, including the energy storage field. However, there is difficulty in product design and development using the finite element method because the mechanical properties of a porous material are different from those of a base material due to the pores. Therefore, in this study, a Python program that can estimate the equivalent property of a material with pores was developed and its matching was verified through comparison with the measurement results. For high-efficiency calculation, the pores were assumed to be circular or elliptical, and they were also assumed to be equally distributed in each direction. The material with pores was assumed to be an orthotropic material, and its equivalent mechanical properties were calculated using the equivalent strain and equivalent stress by using the appropriate material property matrix. The material properties of a specimen with the simulated pores were measured using UTM, and the results were compared with the simulation results to confirm that the degree of matching achieved 6.4%. It is expected that this study will contribute to the design and development of a product in the industrial field.

Heterogeneously-Integrated Optical Phase Shifters for Next-Generation Modulators and Switches on a Silicon Photonics Platform: A Review.

The realization of a silicon optical phase shifter marked a cornerstone for the development of silicon photonics, and it is expected that optical interconnects based on the technology relax the explosive datacom growth in data centers. High-performance silicon optical modulators and switches, integrated into a chip, play a very important role in optical transceivers, encoding electrical signals onto the light at high speed and routing the optical signals, respectively. The development of the devices is continuously required to meet the ever-increasing data traffic at higher performance and lower cost. Therefore, heterogeneous integration is one of the highly promising approaches, expected to enable high modulation efficiency, low loss, low power consumption, small device footprint, etc. Therefore, we review heterogeneously integrated optical modulators and switches for the next-generation silicon photonic platform.

V-Set and Immunoglobulin Domain-Containing 1 (VSIG1), Predominantly Expressed in Testicular Germ Cells, Is Dispensable for Spermatogenesis and Male Fertility in Mice.

To elucidate the functional role of V-set and immunoglobulin domain-containing 1 (VSIG1) in spermatogenesis and fertilization, we knocked out (KO) VSIG1 in a mouse embryo using CRISPR/Cas9 (Clustered regularly interspaced short palindromic repeat/CRISPR-associated protein 9) -mediated genome editing. Reverse transcription PCR was performed using cDNA synthesized from VSIG1 KO testis RNA. Although Western blot analysis using a specific antibody to VSIG1 confirmed VSIG1 protein defects in the KO mice, hematoxylin-eosin staining analysis was similar in the KO and wild-type mice. Additionally, computer-assisted sperm analysis and in vitro fertilization experiments were conducted to confirm the activity and fertilization ability of sperm derived from the KO mouse. Mice lacking VSIG1 were viable and had no serious developmental defects. As they got older, the KO mice showed slightly higher weight loss, male mice lacking VSIG1 had functional testes, including normal sperm number and motility, and both male and female mice lacking VSIG1 were fertile. Our results from VSIG1 KO mice suggest that VSIG1 may not play essential roles in spermatogenesis and normal testis development, function, and maintenance. VSIG1 in sperm is dispensable for spermatogenesis and male fertility in mice. As several genes are known to possess slightly different functions depending on the species, the importance and molecular mechanism of VSIG1 in tissues of other species needs further investigation.