Prohibitin 2 Is an Inner Mitochondrial Membrane Mitophagy Receptor.

The removal of unwanted or damaged mitochondria by autophagy, a process called mitophagy, is essential for key events in development, cellular homeostasis, tumor suppression, and prevention of neurodegeneration and aging. However, the precise mechanisms of mitophagy remain uncertain. Here, we identify the inner mitochondrial membrane protein, prohibitin 2 (PHB2), as a crucial mitophagy receptor involved in targeting mitochondria for autophagic degradation. PHB2 binds the autophagosomal membrane-associated protein LC3 through an LC3-interaction region (LIR) domain upon mitochondrial depolarization and proteasome-dependent outer membrane rupture. PHB2 is required for Parkin-induced mitophagy in mammalian cells and for the clearance of paternal mitochondria after embryonic fertilization in C. elegans. Our findings pinpoint a conserved mechanism of eukaryotic mitophagy and demonstrate a function of prohibitin 2 that may underlie its roles in physiology, aging, and disease.

HSF-1 regulators DDL-1/2 link insulin-like signaling to heat-shock responses and modulation of longevity.

Extended longevity is often correlated with increased resistance against various stressors. Insulin/IGF-1-like signaling (IIS) is known to have a conserved role in aging and cellular mechanisms against stress. In C. elegans, genetic studies suggest that heat-shock transcription factor HSF-1 is required for IIS to modulate longevity. Here, we report that the activity of HSF-1 is regulated by IIS. This regulation occurs at an early step of HSF-1 activation via two HSF-1 regulators, DDL-1 and DDL-2. Inhibition of DDL-1/2 increases longevity and thermotolerance in an hsf-1-dependent manner. Furthermore, biochemical analyses suggest that DDL-1/2 negatively regulate HSF-1 activity by forming a protein complex with HSF-1. The formation of this complex (DHIC) is affected by the phosphorylation status of DDL-1. Both the formation of DHIC and the phosphorylation of DDL-1 are controlled by IIS. Our findings point to DDL-1/2 as a link between IIS and the HSF-1 pathway.

Mechanism for plasmon-generated solvated electrons.

Solvated electrons are powerful reducing agents capable of driving some of the most energetically expensive reduction reactions. Their generation under mild and sustainable conditions remains challenging though. Using near-ultraviolet irradiation under low-intensity one-photon conditions coupled with electrochemical and optical detection, we show that the yield of solvated electrons in water is increased more than 10 times for nanoparticle-decorated electrodes compared to smooth silver electrodes. Based on the simulations of electric fields and hot carrier distributions, we determine that hot electrons generated by plasmons are injected into water to form solvated electrons. Both yield enhancement and hot carrier production spectrally follow the plasmonic near-field. The ability to enhance solvated electron yields in a controlled manner by tailoring nanoparticle plasmons opens up a promising strategy for exploiting solvated electrons in chemical reactions.

Structural basis of transcriptional activation by the OmpR/PhoB-family response regulator PmrA.

PmrA, an OmpR/PhoB-family response regulator, triggers gene transcription responsible for polymyxin resistance in bacteria by recognizing promoters where the canonical-35 element is replaced by the pmra-box, representing the PmrA recognition sequence. Here, we report a cryo-electron microscopy (cryo-EM) structure of a bacterial PmrA-dependent transcription activation complex (TAC) containing a PmrA dimer, an RNA polymerase σ70 holoenzyme (RNAPH) and the pbgP promoter DNA. Our structure reveals that the RNAPH mainly contacts the PmrA C-terminal DNA-binding domain (DBD) via electrostatic interactions and reorients the DBD three base pairs upstream of the pmra-box, resulting in a dynamic TAC conformation. In vivo assays show that the substitution of the DNA-recognition residue eliminated its transcriptional activity, while variants with altered RNAPH-interacting residues resulted in enhanced transcriptional activity. Our findings suggest that both PmrA recognition-induced DNA distortion and PmrA promoter escape play crucial roles in its transcriptional activation.

Gold Fluorescence Nanoparticles for Enhanced SERS Detection in Biomedical Sensor Applications: Current Trends and Future Directions.

Nanotechnology has emerged as a pivotal tool in biomedical research, particularly in developing advanced sensing platforms for disease diagnosis and therapeutic monitoring. Since gold nanoparticles are biocompatible and have special optical characteristics, they are excellent choices for surface-enhanced Raman scattering (SERS) sensing devices. Integrating fluorescence characteristics further enhances their utility in real-time imaging and tracking within biological systems. The synergistic combination of SERS and fluorescence enables sensitive and selective detection of biomolecules at trace levels, providing a versatile platform for early cancer diagnosis and drug monitoring. In cancer detection, AuNPs facilitate the specific targeting of cancer biomarkers, allowing for early-stage diagnosis and personalized treatment strategies. The enhanced sensitivity of SERS, coupled with the tunable fluorescence properties of AuNPs, offers a powerful tool for the identification of cancer cells and their microenvironment. This dual-mode detection not only improves diagnostic accuracy but also enables the monitoring of treatment response and disease progression. In drug detection, integrating AuNPs with SERS provides a robust platform for identifying and quantifying pharmaceutical compounds. The unique spectral fingerprints obtained through SERS enable the discrimination of drug molecules even in complex biological matrices. Furthermore, the fluorescence property of AuNPs makes it easier to track medication distribution in real-time, maximizing therapeutic effectiveness and reducing adverse effects. Furthermore, the review explores the role of gold fluorescence nanoparticles in photodynamic therapy (PDT). By using the complementary effects of targeted drug release and light-induced cytotoxicity, SERS-guided drug delivery and photodynamic therapy (PDT) can increase the effectiveness of treatment against cancer cells. In conclusion, the utilization of gold fluorescence nanoparticles in conjunction with SERS holds tremendous potential for revolutionizing cancer detection, drug analysis, and photodynamic therapy. The dual-mode capabilities of these nanomaterials provide a multifaceted approach to address the challenges in early diagnosis, treatment monitoring, and personalized medicine, thereby advancing the landscape of biomedical applications.

Bioresource Polymer Composite for Energy Generation and Storage: Developments and Trends.

The ever-growing demand of human society for clean and reliable energy sources spurred a substantial academic interest in exploring the potential of biological resources for developing energy generation and storage systems. As a result, alternative energy sources are needed in populous developing countries to compensate for energy deficits in an environmentally sustainable manner. This review aims to evaluate and summarize the recent progress in bio-based polymer composites (PCs) for energy generation and storage. The articulated review provides an overview of energy storage systems, e. g., supercapacitors and batteries, and discusses the future possibilities of various solar cells (SCs), using both past research progress and possible future developments as a basis for discussion. These studies examine systematic and sequential advances in different generations of SCs. Developing novel PCs that are efficient, stable, and cost-effective is of utmost importance. In addition, the current state of high-performance equipment for each of the technologies is evaluated in detail. We also discuss the prospects, future trends, and opportunities regarding using bioresources for energy generation and storage, as well as the development of low-cost and efficient PCs for SCs.

Disruption of the beclin 1-BCL2 autophagy regulatory complex promotes longevity in mice.

Autophagy increases the lifespan of model organisms; however, its role in promoting mammalian longevity is less well-established1,2. Here we report lifespan and healthspan extension in a mouse model with increased basal autophagy. To determine the effects of constitutively increased autophagy on mammalian health, we generated targeted mutant mice with a Phe121Ala mutation in beclin 1 (Becn1F121A/F121A) that decreases its interaction with the negative regulator BCL2. We demonstrate that the interaction between beclin 1 and BCL2 is disrupted in several tissues in Becn1 F121A/F121A knock-in mice in association with higher levels of basal autophagic flux. Compared to wild-type littermates, the lifespan of both male and female knock-in mice is significantly increased. The healthspan of the knock-in mice also improves, as phenotypes such as age-related renal and cardiac pathological changes and spontaneous tumorigenesis are diminished. Moreover, mice deficient in the anti-ageing protein klotho 3 have increased beclin 1 and BCL2 interaction and decreased autophagy. These phenotypes, along with premature lethality and infertility, are rescued by the beclin 1(F121A) mutation. Together, our data demonstrate that disruption of the beclin 1-BCL2 complex is an effective mechanism to increase autophagy, prevent premature ageing, improve healthspan and promote longevity in mammals.

Author Correction: Disruption of the beclin 1-BCL2 autophagy regulatory complex promotes longevity in mice.

In this Letter, the graphs in Fig. 2a and c were inadvertently the same owing to a copy and paste error from the original graphs in Prism. The Source Data files containing the raw data were correct. Fig. 2c has been corrected online.

ATF6 is essential for human cone photoreceptor development.

Endoplasmic reticulum (ER) stress and Unfolded Protein Response (UPR) signaling promote the pathology of many human diseases. Loss-of-function variants of the UPR regulator Activating Transcription Factor 6 (ATF6) cause severe congenital vision loss diseases such as achromatopsia by unclear pathomechanisms. To investigate this, we generated retinal organoids from achromatopsia patient induced pluripotent stem cells carrying ATF6 disease variants and from gene-edited ATF6 null hESCs. We found that achromatopsia patient and ATF6 null retinal organoids failed to form cone structures concomitant with loss of cone phototransduction gene expression, while rod photoreceptors developed normally. Adaptive optics retinal imaging of achromatopsia patients carrying ATF6 variants also showed absence of cone inner/outer segment structures but preserved rod structures, mirroring the defect in cone formation observed in our retinal organoids. These results establish that ATF6 is essential for human cone development. Interestingly, we find that a selective small molecule ATF6 signaling agonist restores the transcriptional activity of some ATF6 disease-causing variants and stimulates cone growth and gene expression in patient retinal organoids carrying these variants. These findings support that pharmacologic targeting of the ATF6 pathway can promote human cone development and should be further explored for blinding retinal diseases.

Recent Advances in Bioactive Carbon Nanotubes Based on Polymer Composites for Biosensor Applications.

Recent breakthroughs in the field of carbon nanotubes (CNTs) have opened up unprecedented opportunities for the development of specialized bioactive CNT-polymers for a variety of biosensor applications. The incorporation of bioactive materials, including DNA, aptamers and antibodies, into CNTs to produce composites of bioactive CNTs has attracted considerable attention. In addition, polymers are essential for the development of biosensors as they provide biocompatible conditions and are the ideal matrix for the immobilization of proteins. The numerous applications of bioactive compounds combined with the excellent chemical and physical properties of CNTs have led to the development of bioactive CNT-polymer composites. This article provides a comprehensive overview of CNT-polymer composites and new approaches to encapsulate bioactive compounds and polymers in CNTs. Finally, biosensor applications of bioactive CNT-polymer for the detection of glucose, H2O2 and cholesterol were investigated. The surface of CNT-polymer facilitates the immobilization of bioactive molecules such as DNA, enzymes or antibodies, which in turn enables the construction of state-of-the-art, future-oriented biosensors.

Taiwan ocular inflammation society consensus recommendations for the management of juvenile idiopathic arthritis-associated uveitis.

We presented the development of a consensus guideline for managing juvenile idiopathic arthritis-associated uveitis (JIAU) in Taiwan, considering regional differences in manifestation and epidemiology. The Taiwan Ocular Inflammation Society (TOIS) committee formulated this guideline using a modified Delphi approach with two panel meetings. Recommendations were based on a comprehensive evidence-based literature review and expert clinical experiences, and were graded according to the Oxford Centre for Evidence-Based Medicine's "Levels of Evidence" guideline (March 2009). The TOIS consensus guideline consists of 10 recommendations in four categories: screening and diagnosis, treatment, complications, and monitoring, covering a total of 27 items. These recommendations received over 75% agreement from the panelists. Early diagnosis and a coordinated referral system between ophthalmologists and pediatric rheumatologists are crucial to prevent irreversible visual impairment in children with JIAU. However, achieving a balance between disease activity and medication use remains a key challenge in JIAU management, necessitating further clinical studies.

Prognostic Value of Body Surface Area-Adjusted Oxygen Uptake Efficiency Slope in Heart Failure Patients.

Background: COVID-19 has been associated with a higher risk of developing heart failure (HF). Among the parameters derived from cardiopulmonary exercise testing (CPET), oxygen uptake efficiency slope (OUES) has become one of the most important parameters for predicting the prognosis of HF patients. However, the clinical utilization of OUES is limited owing to its variation with patient height and weight. This study aimed to evaluate the prognostic value of body surface area-adjusted OUES (OUES/BSA) in adults with HF. Methods: Thirty-six HF patients (mean age, 57 ± 12 years; 30 men) undergoing CPET between July 2019 and May 2020 who were followed up for 12 months were enrolled. The endpoints were major cardiovascular (CV) events, including hospitalization due to acute decompensated HF, left ventricular assist device implantation, heart transplantation, and cardiovascular-related death. We analyzed the correlations between clinical/CPET variables and major CV events. Results: Among the analyzed CPET variables, OUES/BSA had better correlation with maximal oxygen uptake (VO2max) than other variables. In univariate Cox proportional analysis, OUES/BSA and peak VO2 were both significant independent prognostic factors. The cutoff value of OUES/BSA was 595 ml/min/m2 with an area under the curve of 0.929. The patients with OUES/BSA < 595 ml/min/m2 had a lower CV event-free survival rate at 12 months of follow-up compared with the other group (33.3% and 100%, respectively; log-rank test, p < 0.001). Conclusions: BSA-adjusted OUES is an effective independent predictor for prognosis in HF patients and can be an alternative to peak VO2 for risk stratification in HF patients, regardless of exercise intensity. However, further large-scale studies are required to validate our findings.

Plasma-Enabled Graphene Quantum Dot Hydrogels as Smart Anticancer Drug Nanocarriers.

One of the major challenges on the way to low-cost, simple, and effective cancer treatments is the lack of smart anticancer drug delivery materials with the requisite of site-specific and microenvironment-responsive properties. This work reports the development of plasma-engineered smart drug nanocarriers (SDNCs) containing chitosan and nitrogen-doped graphene quantum dots (NGQDs) for drug delivery in a pH-responsive manner. Through a customized microplasma processing, a highly cross-linked SDNC with only 4.5% of NGQD ratio can exhibit enhanced toughness up to threefold higher than the control chitosan group, avoiding the commonly used high temperatures and toxic chemical cross-linking agents. The SDNCs demonstrate improved loading capability for doxorubicin (DOX) via π-π interactions and stable solid-state photoluminescence to monitor the DOX loading and release through the Förster resonance energy transfer (FRET) mechanism. Moreover, the DOX loaded SDNC exhibits anticancer effects against cancer cells during cytotoxicity tests at minimum concentration. Cellular uptake studies confirm that the DOX loaded SDNC can be successfully internalized into the nucleus after 12 h incubation period. This work provides new insights into the development of smart, environmental-friendly, and biocompatible nanographene hydrogels for the next-generation biomedical applications.

Electro-optic properties of liquid crystal cells with nanowall electrodes.

This work fabricates a nanowall electrode for achieving advanced liquid crystal (LC) devices and improving LC displays. The nanowall electrode consists of indium-tin-oxide (ITO) sheets stacked with nanowalls, and the nanowalls have a height and thickness of 4 µm and 500 nm, respectively. The high aspect ratio (8.0) of the nanowalls sets the nanowall electrode apart from previous electrodes. A flat electrode that comprises only ITO sheets is used to evaluate the nanowall electrode. The LC cell with the nanowall electrode exhibits better electro-optic properties than the LC cell with the flat electrode due to the strong transverse electric field and small subelectrode gap of the nanowall electrode. Especially, the operating voltage (3.7 V) of the nanowall cell is 36% smaller than that (5.8 V) of the flat cell. Therefore, nanowall electrodes have potential in LC lenses, LC antennas, metaverse displays, and digital optics.

Phocaeicola oris sp. nov., an anaerobic bacterium isolated from the saliva of a patient with oral squamous cell carcinoma.

A Gram-stain-negative or -positive, strictly anaerobic, non-spore-forming and pleomorphic bacterium (designated 14-104T) was isolated from the saliva sample of a patient with oral squamous cell carcinoma. It was an acid-tolerant neutralophilic mesophile, growing at between 20 and 40 °C (with optimum growth at 30 °C) and pH between pH 3.0 and 7.0 (with optimum growth at pH 6.0-7.0). It contained anteiso-C15 : 0 and C15 : 0 as the major fatty acids. The genome size of strain 14-104T was 2.98 Mbp, and the G+C content was 39.6 mol%. It shared <87 % 16S rRNA sequence similarity, <71 % orthologous average nucleotide identity, <76 % average amino acid identity and <68 %% of conserved proteins with its closest relative, Phocaeicola abscessus CCUG 55929T. Reconstruction of phylogenetic and phylogenomic trees revealed that strain 14-104T and P. abscessus CCUG 55929T were clustered as a distinct clade without any other terminal node. The phylogenetic and phylogenomic analyses along with physiological and chemotaxonomic data indicated that strain 14-104T represents a novel species in the genus Phocaeicola, for which the name Phocaeicola oris sp. nov. is proposed. The type strain is 14-104T (=BCRC 81305T= NBRC 115041T).

Exploring the Advantages of Quantum Generative Adversarial Networks in Generative Chemistry.

De novo drug design with desired biological activities is crucial for developing novel therapeutics for patients. The drug development process is time- and resource-consuming, and it has a low probability of success. Recent advances in machine learning and deep learning technology have reduced the time and cost of the discovery process and therefore, improved pharmaceutical research and development. In this paper, we explore the combination of two rapidly developing fields with lead candidate discovery in the drug development process. First, artificial intelligence has already been demonstrated to successfully accelerate conventional drug design approaches. Second, quantum computing has demonstrated promising potential in different applications, such as quantum chemistry, combinatorial optimizations, and machine learning. This article explores hybrid quantum-classical generative adversarial networks (GAN) for small molecule discovery. We substituted each element of GAN with a variational quantum circuit (VQC) and demonstrated the quantum advantages in the small drug discovery. Utilizing a VQC in the noise generator of a GAN to generate small molecules achieves better physicochemical properties and performance in the goal-directed benchmark than the classical counterpart. Moreover, we demonstrate the potential of a VQC with only tens of learnable parameters in the generator of GAN to generate small molecules. We also demonstrate the quantum advantage of a VQC in the discriminator of GAN. In this hybrid model, the number of learnable parameters is significantly less than the classical ones, and it can still generate valid molecules. The hybrid model with only tens of training parameters in the quantum discriminator outperforms the MLP-based one in terms of both generated molecule properties and the achieved KL divergence. However, the hybrid quantum-classical GANs still face challenges in generating unique and valid molecules compared to their classical counterparts.

Cytomegalovirus Uveitis: Taiwan expert consensus.

Cytomegalovirus (CMV) uveitis, a type of herpetic uveitis, is a major cause of infectious uveitis. Anterior and posterior CMV uveitis have diverse clinical presentations and treatment modalities. Based on expert consensus in Taiwan, this article provides suggestions regarding clinical manifestations, diagnosis, and treatment strategies for CMV uveitis based on clinical practice experience in Taiwan. CMV uveitis may have a distinct clinical presentation. Polymerase chain reaction (PCR) is an essential diagnostic tool to confirm a diagnosis. Antiviral therapy is the mainstay of treatment. Different agents, routes, and other supplemental treatments have been summarized and discussed in this article. Early diagnosis and appropriate treatment of CMV uveitis are crucial to avoid irreversible complications and vision loss. This consensus provides practical guidelines for ophthalmologists in Taiwan.

Time attitudes affecting psychological health during COVID-19 pandemic: a two-wave, six-month prospective study in Taiwan.

The COVID-19 pandemic has induced traumatic and fear responses globally. Time attitudes, which refer to one's feelings toward the past, present and future, may have certain effects on psychological adaptations during this crisis period. This study employed a person-centered approach and a two-wave prospective design to investigate how people with different time attitude profiles change differently in their PTSD symptoms and COVID-19-related fears from a low-risk stage to the first big COVID-19 outbreak in Taiwan. Participants were 354 adults with a mean age of 27.79 years. The result provided support for the theoretical six-factor structure of the traditional Chinese Adolescent and Adult Time Inventory-Time Attitudes Scale (AATI-TA). Four clusters of time attitude profiles were identified (Positives, Negatives, Past Negatives and Pessimists). At both waves, Positives had lower levels of PTSD severity and COVID-19-related fears than most of the other groups, and the reverse was noted for Negatives. As for time effects, people across all profiles were significantly affected during the outbreak, but Negatives showed a greater increase in PTSD severity than other groups. In conclusion, mental health services should put efforts into early identification of those with highly negative time attitudes and implement interventions that nudge people toward a more balanced or positive attitude in each temporal frame, especially during adversity such as the COVID-19 pandemic.

Spin-Enhanced Lateral Flow Immunoassay for High-Sensitivity Detection of Nonstructural Protein NS1 Serotypes of the Dengue Virus.

Dengue fever is a global mosquito-borne viral infectious disease that has, in recent years, rapidly spread to almost all regions of the world. Lack of vaccination and directed treatment makes detection at the infection's early stages extremely important for disease prevention and clinical care. In this paper, we developed a rapid and highly sensitive dengue detection tool using a novel platform of diagnosis, called spin-enhanced lateral flow immunoassay (SELFIA) with a fluorescent nanodiamond (FND) as a reporter. Taking advantage of the unique magneto-optical properties of negatively charged nitrogen-vacancy centers in the FND, the SELFIA platform utilizes alternating electromagnetic fields to modulate signals from FND's fluorescence to provide sensitive and specific results. With sandwich SELFIA, we could efficiently detect all four dengue non-structural protein (NS1) serotypes (DV1, DV2, DV3, and DV4). The lowest detection concentration of the dengue NS1 antigens varied from 0.1 to 1.3 ng/mL, which is among the lowest limits of detection to date. The FND-based SELFIA technique is up to 500 and 5000 times more sensitive than carbon black and conventional gold nanoparticles, respectively. By using different anti-NS1 antibodies, we could differentiate the NS1 antigen serotypes contained in the tested samples via three simultaneous assays. Proposed SELFIA allows for both qualitative and quantitative differentiation between different NS1 protein serotypes, which will assist in the development of a highly sensitive and specific detection platform for dengue screening that has the potential to detect the disease at its early stages, especially in high-risk and limited-resource areas.

Mitophagy in aging and longevity.

The clearance of damaged or unwanted mitochondria by autophagy (also known as mitophagy) is a mitochondrial quality control mechanism postulated to play an essential role in cellular homeostasis, metabolism, and development and confers protection against a wide range of diseases. Proper removal of damaged or unwanted mitochondria is essential for organismal health. Defects in mitophagy are associated with Parkinson's, Alzheimer's disease, cancer, and other degenerative disorders. Mitochondria regulate organismal fitness and longevity via multiple pathways, including cellular senescence, stem cell function, inflammation, mitochondrial unfolded protein response (mtUPR), and bioenergetics. Thus, mitophagy is postulated to be pivotal for maintaining organismal healthspan and lifespan and the protection against aged-related degeneration. In this review, we will summarize recent understanding of the mechanism of mitophagy and aspects of mitochondrial functions. We will focus on mitochondria-related cellular processes that are linked to aging and examine current genetic evidence that supports the hypothesis that mitophagy is a pro-longevity mechanism.