Pharmaceutical innovation and advanced biotechnology in the biotech-pharmaceutical industry for antibody-drug conjugate development.

Antibody-drug conjugates (ADCs), from prototypes in the 1980s to first- and second-generation products in the 2000s, and now in their multiformats, have progressed tremendously to meet oncological challenges. Currently, 13 ADCs have been approved for medical practice, with over 200 candidates in clinical trials. Moreover, ADCs have evolved into different formats, including bispecific ADCs, probody-drug conjugates, pH-responsive ADCs, target-degrading ADCs, and immunostimulating ADCs. Technologies from biopharmaceutical industries have a crucial role in the clinical transition of these novel biotherapeutics. In this review, we highlight several features contributing to the prosperity of bioindustrial ADC development. Various proprietary technologies from biopharmaceutical companies are discussed. Such advances in biopharmaceutical industries are the backbone for the success of ADCs in development and clinical application.

Overexpression of arginase gene CAR1 renders yeast Saccharomyces cerevisiae acetic acid tolerance.

Acetic acid is a common inhibitor present in lignocellulose hydrolysate, which inhibits the ethanol production by yeast strains. Therefore, the cellulosic ethanol industry requires yeast strains that can tolerate acetic acid stress. Here we demonstrate that overexpressing a yeast native arginase-encoding gene, CAR1, renders Saccharomyces cerevisiae acetic acid tolerance. Specifically, ethanol yield increased by 27.3% in the CAR1-overexpressing strain compared to the control strain under 5.0 g/L acetic acid stress. The global intracellular amino acid level and compositions were further analyzed, and we found that CAR1 overexpression reduced the total amino acid content in response to acetic acid stress. Moreover, the CAR1 overexpressing strain showed increased ATP level and improved cell membrane integrity. Notably, we demonstrated that the effect of CAR1 overexpression was independent of the spermidine and proline metabolism, which indicates novel mechanisms for enhancing yeast stress tolerance. Our studies also suggest that CAR1 is a novel genetic element to be used in synthetic biology of yeast for efficient production of fuel ethanol.

Failure of Lithium-Ion Batteries Accelerated by Gravity.

The safety concerns surrounding lithium-ion batteries (LIBs) have garnered increasing attention due to their potential to endanger lives and incur significant financial losses. However, the origins of battery failures are diverse, presenting significant challenges in developing safety measures to mitigate accidental catastrophes. In this study, the aging mechanism of LiNi0.5Co0.2Mn0.3O2||graphite-based cylindrical 18,650 LIBs stored at room temperature for two years was investigated. It was found that an uneven distribution of electrolytes can be caused by gravity, leading to temperature variations within the battery. Specifically, it was observed that the temperature at the top of the battery was approximately -0.89 °C higher than at the bottom, correlating with an increase in partial internal resistance. Additionally, upon disassembly and analysis of spent batteries, the most significant damage to electrode materials at the top of the battery was observed. These findings suggest that gravity-induced electrolyte insufficiency exacerbates side reactions, particularly at the top of the battery. This study offers a unique perspective on the safety concerns associated with high-energy-density batteries in long-term and large-scale applications.

Dynamic flyer in barrel imaging via high intensity short-pulse laser.

The thin flyer is a small-scale flying object, which is well known as the core functional element of the initiator. Understanding how flyers perform has been a long-standing issue in detonator science. However, it remains a significant challenge to explore how the flyer is formed and functions in the barrel of the initiator via tabletop devices. In this study, we present dynamic and unprecedented images of flyer in barrel via high intensity short-pulse laser. Advanced radiography, coupled with a high-intensity picosecond laser X-ray source, has enabled the provision of state-of-the-art radiographs in a single-shot experiment for observing micron-scale flyer formation in a hollow cylinder in nanoseconds. The flyer was clearly visible in the barrel and was accelerated and restricted differently from that without the barrel. This first implementation of a tabletop X-ray source provided a new approach for capturing dynamic photographs of small-scale flying objects, which were previously reported to be accessible only via an X-ray phase-contrast imaging system at the advanced photon source. These efforts have led to a significant improvement of radiographic capability and a greater understanding of the mechanisms of "burst" of exploding foil initiators for this application.

Sub-millisecond lithiothermal synthesis of graphitic meso-microporous carbon.

Porous carbons with concurrently high specific surface area and electronic conductivity are desirable by virtue of their desirable electron and ion transport ability, but conventional preparing methods suffer from either low yield or inferior quality carbons. Here we developed a lithiothermal approach to bottom-up synthesize highly meso-microporous graphitized carbon (MGC). The preparation can be finished in a few milliseconds by the self-propagating reaction between polytetrafluoroethylene powder and molten lithium (Li) metal, during which instant ultra-high temperature (>3000 K) was produced. This instantaneous carbon vaporization and condensation at ultra-high temperatures and in ultra-short duration enable the MGC to show a highly graphitized and continuously cross-coupled open pore structure. MGC displays superior electrochemical capacitor performance of exceptional power capability and ultralong-term cyclability. The processes used to make this carbon are readily scalable to industrial levels.

Novel Isoalantolactone-Based Derivatives as Potent NLRP3 Inflammasome Inhibitors: Design, Synthesis, and Biological Characterization.

The NLRP3 inflammasome has been recognized as a promising therapeutic target in drug discovery for inflammatory diseases. Our initial research identified a natural sesquiterpene isoalantolactone (IAL) as the active scaffold targeting NLRP3 inflammasome. To improve its activity and metabolic stability, a total of 64 IAL derivatives were designed and synthesized. Among them, compound 49 emerged as the optimal lead, displaying the most potent inhibitory efficacy on nigericin-induced IL-1ß release in THP-1 cells, with an IC50 value of 0.29 µM, approximately 27-fold more potent than that of IAL (IC50: 7.86 µM), and exhibiting higher metabolic stability. Importantly, 49 remarkably improved DSS-induced ulcerative colitis in vivo. Mechanistically, we demonstrated that 49 covalently bound to cysteine 279 in the NACHT domain of NLRP3, thereby inhibiting the assembly and activation of NLRP3 inflammasome. These results provided compelling evidence to further advance the development of more potent NLRP3 inhibitors based on this scaffold.

High quality holographic 3D display with enhanced focus cues based on multiple directional light reconstruction.

Holographic display faces the trade-off between image quality and focus cues, resulting from the specific choice of phase distribution. In this Letter, we propose a speckle-free holographic display with enhanced focus cues by multiple directional light reconstruction. The uniform phase hologram is first generated by the gradient descent optimization algorithm. The blazed grating phase is used to steer the object light to a specific direction. Multiple sub-holograms with different blazed gratings are refreshed fast to reconstruct the images from different directions. Thus, the defocus blur is improved due to the separation of multiple spots on the defocus plane. The multi-plane reconstruction is also realized by pre-processing the depth images to eliminate image separation. The proposed method provides apparent focus cues while maintaining high image qualities, which is expected to realize comfortable holographic near-eye display in the near future.

Combination of Albumin/Fibrinogen Ratio and Admission Hunt-Hess Scale Score as an Independent Predictor of Clinical Outcome in Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: The albumin/fibrinogen ratio (AFR) is an independent predictor of clinical outcomes of some diseases; however, the prognostic value of AFR and the admission Hunt-Hess (HH) score is still unclear for patients with an aneurysmal subarachnoid hemorrhage (aSAH). This study aimed to assess the relationship between the AFR-HH score and 6-month outcomes of aSAH patients. METHODS: The clinical characteristics of aSAH patients admitted to our department between December 2017 and December 2021 were retrospectively analyzed. The candidate risk factors were screened using univariate regression analysis, and the independence of the resultant risk factors was evaluated by binary logistic regression analysis. The predictive value of the combined AFR and HH score for unfavorable outcomes was assessed using receiver operating characteristic curve analysis. RESULTS: A total of 112 aSAH patients were included. Binary logistic regression analysis showed the perioperative period AFR, Glasgow coma scale score, and admission HH score were independent risk factors for unfavorable outcomes for aSAH patients. The receiver operating characteristic curve analysis showed the predictive capacity of AFR plus the admission HH score outperformed the AFR, Glasgow coma scale score, and admission HH scale alone and the combination of the AFR and Glasgow coma scale score. CONCLUSIONS: A low AFR during the perioperative period is associated with unfavorable outcomes for aSAH patients at 6 months. The combination of the AFR and admission HH scale score provides superior predictive capacity to either the AFR or HH scale score alone.

Lens array-based holographic 3D display with an expanded field of view and eyebox.

Conventional spatial light modulator (SLM)-based holographic 3D display faces limited field of view (FOV) and eyebox, due to its limited pixel number. In this paper, a lens array is used to expand the FOV and eyebox of an SLM-based holographic display. The hologram is calculated to reconstruct a 3D sub-image array, each sub-image corresponding to a specific perspective of the 3D object. Then, the 3D sub-image array is imaged and magnified by the lens array to integrate to the original 3D image. The FOV is expanded due to the large numerical aperture of the lens, and the eyebox is expanded because the lens array generates multiple viewpoints with a large pitch. The optical experiment realizes a 17.6° FOV and 50 mm eyebox, which contains 4 × 4 viewpoints. Apparent motion parallax is observed through the viewpoint array, which is usually hard to observe in a conventional SLM-based holographic display. The proposed method provides a novel, to the best of our knowledge, way to expand the FOV and eyebox of holographic 3D display without increasing the total pixel number of the SLM.

Oriented Gradient Doping of Zirconium in Ni-Rich Cathode to Achieve Ultrahigh Stability and Rate Capability.

Ni-rich layered oxide materials exhibit great prospects for practical applications in lithium-ion batteries due to their high specific capacity. However, the poor cycling performance and suboptimal rate performance have caused obstacles for their widespread application. Herein, we developed a gradient Zr element doping method based on the bulk gradient concentration of Ni-rich layered oxide material to reinforce the cycle stability and rate performance of the cathode. In particular, the orientations of the gradient Zr doping were achieved via coprecipitation in a positive or negative correlation between the concentrations of Zr and Ni, and it was revealed that the material behaves better when the Zr content is abundant in the core. The gradient doping of Zr decreases the content of Ni2+ and mitigates the mixing degree of Li+ and Ni2+, implying the superior performance of doped cathode material. Compared with the bare sample (70.7%, 121.4 mAh g-1), the Zr-doped sample delivered a higher capacity retention of 85.6% after 300 cycles at 1C (1C = 180 mA g-1) and exhibited a considerable rate performance of 122.5 mAh g-1 at 20C. In particular, the Zr-doped cathodes performed dramatically on high rate cycling at 10C, with an initial capacity of 143.6 and 103.9 mAh g-1 after 300 cycles. Furthermore, the Zr-doped cathode delivered significant stability at a high potential of 4.5 V with a capacity retention of 72.1% after 300 cycles, while that of the bare sample was only 37.4%. The concept of gradient doping strategies during coprecipitation offers new insight into the design of advanced cathodes with excellent cycling stability and rate capability.

[Effect of High-Concentration Uric Acid on Nitric Oxide].

Uric acid (UA) is the final product of purine metabolism in human body,and its metabolic disorder will induce hyperuricemia (HUA).The occurrence and development of HUA are associated with a variety of pathological mechanisms such as oxidative stress injury,activation of inflammatory cytokines,and activation of renin-angiotensin-aldosterone system.These mechanisms directly or indirectly affect the bioavailability of endogenous nitric oxide (NO).The decrease in NO bioavailability is common in the diseases with high concentration of UA as an independent risk factor.In this review,we summarize the mechanisms by which high concentrations of UA affect the endogenous NO bioavailability,with a focus on the mechanisms of high-concentration UA in decreasing the synthesis and/or increasing the consumption of NO.This review aims to provide references for alleviating the multisystem symptoms and improving the prognosis of HUA,and lay a theoretical foundation for in-depth study of the correlations between HUA and other metabolic diseases.

Membrane phospholipid peroxidation promotes loss of dopaminergic neurons in psychological stress-induced Parkinson's disease susceptibility.

Parkinson's disease (PD) is a neurodegenerative disorder associated with α-synuclein aggregation and dopaminergic neuron loss in the midbrain. There is evidence that psychological stress promotes PD progression by enhancing glucocorticoids-related oxidative damage, however, the mechanisms involved are unknown. The present study demonstrated that plasma membrane phospholipid peroxides, as determined by phospholipidomics, triggered ferroptosis in dopaminergic neurons, which in turn contributed to stress exacerbated PD-like motor disorder in mice overexpressing mutant human α-synuclein. Using hormonomics, we identified that stress stimulated corticosteroid release and promoted 15-lipoxygenase-1 (ALOX15)-mediated phospholipid peroxidation. ALOX15 was upregulated by α-synuclein overexpression and acted as a fundamental risk factor in the development of chronic stress-induced parkinsonism and neurodegeneration. Further, we demonstrated the mechanism by which corticosteroids activated the PKC pathway and induced phosphatidylethanolamine-binding protein-1 (PEBP1) to form a complex with ALOX15, thereby facilitating ALOX15 to locate on the plasma membrane phospholipids. A natural product isolated from herbs, leonurine, was screened with activities of inhibiting the ALOX15/PEBP1 interaction and thereby attenuating membrane phospholipid peroxidation. Collectively, our findings demonstrate that stress increases the susceptibility of PD by driving membrane lipid peroxidation of dopaminergic neurons and suggest the ALOX15/PEBP1 complex as a potential intervention target.

Universality of Benzoquinone-based Anodes toward Various Metal Cations in Aqueous Rechargeable Batteries.

The poly(2,5-dihydroxy-1,4-benzoquinone-3,6-methylene) (denoted as PDBM) capable of reversible coordination/uncoordination with both mono- and multivalent cations in aqueous electrolytes is desired to develop safe, sustainable, and cost-effective aqueous rechargeable batteries (ARBs). However, the comprehensive mechanism between the electrochemical performance of PDBM and properties of these metal cations is unclear. Herein, we initially demonstrate the universality of PDBM to reversibly coordinate/uncoordinate with various cations (Na+, Mg2+, Ca2+, Zn2+, Al3+, etc.) with high specific capacities (>200 mA h g-1), high rate capabilities (∼20 C), and long cycling life (5000 cycles). Additionally, an unprecedented ion-coordination mechanism is presented: the monovalent cations prefer to occupy the in-plane sites with respect to the benzene rings of PDBM during the electrochemical reduced process, while the multivalent cations with the larger charge density tend to occupy the out-of-plane sites, which can use more active sites in the PDBM molecule and deliver the higher specific capacities. Meanwhile, the redox potential of PDBM decreases with the decrease in the binding energy between metal cations and PDBM molecules. The universality of PDBM to numerous cations is beneficial to design high-safety, low-cost, and long-lifespan ARBs for large-scale energy storage systems by modulating the aqueous electrolytes.

Lomatogonium rotatum extract alleviates diabetes mellitus induced by a high-fat, high-sugar diet and streptozotocin in rats.

BACKGROUND: Lomatogonium rotatum (LR) is traditionally used in Mongolian folk medicine as a hypoglycemic agent, but its evidence-based pharmacological effects and me-chanisms of action have not been fully elucidated. AIM: To emphasize the hypoglycemic action mechanism of LR in a type 2 diabetic rat model and examine potential biomarkers to obtain mechanistic understanding regarding serum metabolite modifications. METHODS: A high-fat, high-sugar diet and streptozotocin injection-induced type 2 diabetic rat model was established. The chemical composition of the LR was identified by high performance liquid chromatography. LR extract administrated as oral gavage at 0.5 g/kg, 2.5 g/kg, and 5 g/kg for 4 wk. Anti-diabetic effects of LR extract were evaluated based on histopathological examination as well as the measurement of blood glucose, insulin, glucagon-like peptide 1 (GLP-1), and lipid levels. Serum metabolites were analyzed using an untargeted metabolomics approach. RESULTS: According to a chemical analysis, swertiamarin, sweroside, hesperetin, coumarin, 1.7-dihydroxy-3,8-dimethoxyl xanthone, and 1-hydroxy-2,3,5 trimethoxanone are the principal active ingredients in LR. An anti-diabetic experiment revealed that the LR treatment significantly increased plasma insulin and GLP-1 levels while effectively lowering blood glucose, total cholesterol, triglycerides, low-density lipoprotein cholesterol, and oral glucose tolerance test compared to the model group. Furthermore, untargeted metabolomic analysis of serum samples detected 236 metabolites, among which 86 were differentially expressed between the model and the LR group. It was also found that LR considerably altered the levels of metabolites such as vitamin B6, mevalonate-5P, D-proline, L-lysine, and taurine, which are involved in the regulation of the vitamin B6 metabolic pathway, selenium amino acid metabolic pathway, pyrimidine metabolic pathway, and arginine and proline metabolic pathways. CONCLUSION: These findings indicated that LR may have a hypoglycemic impact and that its role may be related to changes in the serum metabolites and to facilitate the release of insulin and GLP-1, which lower blood glucose and lipid profiles.

Clinical and genetic features of Kenny-Caffey syndrome type 2 with multiple electrolyte disturbances: A case report.

BACKGROUND: Hypoparathyroidism, which can be sporadic or a component of an inherited syndrome, is the most common cause of hypocalcemia. If hypocalcemia is accompanied by other electrolyte disturbances, such as hypokalemia and hypomagnesemia, then the cause, such as renal tubular disease, should be carefully identified. CASE SUMMARY: An 18-year-old female visited our clinic because of short stature and facial deformities, including typical phenotypes, such as low ear position, depression of the nasal bridge, small hands and feet, and loss of dentition. The lab results suggested normal parathyroid hormone but hypocalcemia. In addition, multiple electrolyte disturbances were found, including hypokalemia, hypocalcemia and hypomagnesemia. The physical signs showed a short fourth metatarsal bone of both feet. The X-ray images showed cortical thickening of long bones and narrowing of the medulla of the lumen. Cranial computed tomography indicated calcification in the bilateral basal ganglia. Finally, the genetic investigation showed a de novo heterogenous mutation of "FAM111A" (c. G1706A:p.R569H). Through a review of previously reported cases, the mutation was found to be the most common mutation site in Kenny-Caffey syndrome type 2 (KCS2) cases reported thus far (16/23, 69.6%). The mutation was slightly more prevalent in females than in males (11/16, 68.8%). Except for hypocalcemia, other clinical manifestations are heterogeneous. CONCLUSION: As a rare autosomal dominant genetic disease of hypoparathyroidism, the clinical manifestations of KCS2 are atypical and diverse. This girl presented with short stature, facial deformities and skeletal deformities. The laboratory results revealed hypocalcemia as the main electrolyte disturbance. Even though her family members showed normal phenotypes, gene detection was performed to find the mutation of the FAM111A gene and confirmed the diagnosis of KCS2.

Cross talk-free retinal projection display based on a holographic complementary viewpoint array.

In near-eye displays (NEDs), retinal projection display (RPD) is one kind of promising technology to alleviate the vergence-accommodation conflict (VAC) issue due to its always-in-focus feature. Viewpoint replication is widely used to enlarge the limited eyebox. However, the mismatch between viewpoint interval and eye pupil diameter will cause the inter-viewpoint cross talk when multiple viewpoints enter the pupil simultaneously. In this Letter, a holographic complementary viewpoint method is proposed to solve this cross talk problem. Instead of avoiding observing multiple viewpoint images simultaneously, it is designed that multiple complementary viewpoints jointly project the complete image on the retina without cross talk. To do this, the target image is segmented into multiple sub-images, each multiplied with a corresponding partial spherical phase to converge to a specific complementary viewpoint. A group of complementary viewpoint enter the eye pupil simultaneously, and each viewpoint project a corresponding sub-image on a specific area of the retina and splice to a complete image. All of the complementary viewpoints are duplicated to an interlaced two-dimensional array to extend the eyebox in both horizontal and vertical directions. Optical experiment verifies that the proposed method could present smooth transition between viewpoints to avoid both inter-viewpoint cross talk and blank image issues.

Midbrain dopamine oxidation links ubiquitination of glutathione peroxidase 4 to ferroptosis of dopaminergic neurons.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the gradual loss of midbrain dopaminergic neurons in association with aggregation of α-synuclein. Oxidative damage has been widely implicated in this disease, though the mechanisms involved remain elusive. Here, we demonstrated that preferential accumulation of peroxidized phospholipids and loss of the antioxidant enzyme glutathione peroxidase 4 (GPX4) were responsible for vulnerability of midbrain dopaminergic neurons and progressive motor dysfunctions in a mouse model of PD. We also established a mechanism wherein iron-induced dopamine oxidation modified GPX4, thereby rendering it amenable to degradation via the ubiquitin-proteasome pathway. In conclusion, this study unraveled what we believe to be a novel pathway for dopaminergic neuron degeneration during PD pathogenesis, driven by dopamine-induced loss of antioxidant GPX4 activity.

Effects of plant community and altitude on food composition of Cervus elaphus wallichii during the withered grass period on the Tibetan Plateau, China.

How Tibetan red deer (Cervus elaphus wallichii) acclimates to high altitude environment during the withered grass period is one of the challenges in maintaining their nutrient intake. It is an important basis to study the nutritional ecology of wild large ungulates in alpine ecosystems by investigating the changes in plant communities with altitude during the withered grass period and how these changes affect the food composition of Tibetan red deer. In this study, we selected the Tibetan red deer in Sangri County, Shannan region of Tibet as the research subject. We carried out field surveys on the altitude, plant communities, and feeding traces of the Tibetan red deer in March of 2021 and 2022 during the withered grass period on the Tibetan Plateau. Detrended correspondence analysis and canonical correspondence analysis were used to study altitudinal variations in plant communities and the regularity of food composition. The results showed that during the period of withered grass, Tibetan red deer ate primarily Salix daltoniana, Rosa macrophylla var. glandulifera and Dasiphora parvifolia. S. daltoniana accounted for more than 50% of the food composition, as the main food resources for red deer in withered grass period. In the low altitude area (4100-4300 m), plant community included Caragana versicolor, R. macrophylla and Berberis temolaica, and Tibetan red deer mainly ate R. macrophylla, C. versicolor and Artemisia wellbyi. In higher altitude area (4300-4600 m), plant community consisted of Rhododendron nivale, Rhododendron fragariiflorum, and Sibiraea angustata, and Tibetan red deer mainly fed on S. daltoniana, Salix obscura, and Carex littledalei. At different altitudes, the dominant plant species were the main food of Tibetan red deer. It is suggested that the changes of plant community composition with altitude directly affected food composition of Tibetan red deer, indicating different food composition patterns with altitude gradients.