A temperature-regulated bioorthogonal reaction to target lysine:Hemiacetal pharmacophore in genipin irreversibly binds with UCP2,inhibiting mitochondrial thermogenesis

Mitochondria are essential for eukaryotic life as powerhouses for energy metabolism. Excessive mitochondrial hyperthermia and reactive oxygen species(ROS) production have been associated with aging, cancer,neurodegenerative diseases, and other disorders. Uncoupling protein 2(UCP2) is the effector responsible for regulating cellular thermogenesis and ROS production via dissipating protons in an electrochemical gradient. A UCP2 inhibitor named genipin(GNP) is being researched for its effect on mitochondrial temperature, but little is known about its mechanisms. This study developed several molecular probes to explore the interactions between GNP and UCP2. The result indicated that the hemiacetal structure in GNP could selectively react with the ?-amine of lysine on the UCP2 proton leakage channel through ringopening condensation at the mitochondrial, cellular, and animal levels. A notable feature of the reaction is its temperature sensitivity and ability to conjugate with UCP2 at high fever as lysine-specific covalent inhibitors that prevent mitochondrial thermogenesis. The result not only clarifies the existence of an antipyretic properties of GNP via its irreversible coupling to UCP2, but also reveals a bioorthogonal reaction of hemiacetal iridoid aglycone for selectively binding with the ?-amine of lysine on proteins.

Multiple sclerosis drug repurposing for neuroregeneration

Multiple sclerosis(MS)is an autoimmune disorder of the central nervous system(CNS)and is primarily characterized by immune cell infiltration leading to relapses followed by remission phases and a disease course turning progressive over time with neurodegenerative processes taking over(Amin and Hersh,2023).Of note,beyond relapse-associated worsening early in disease progression independent of relapse activity may arise independently of relapse activity and can occur in all phenotypes.Autoimmune-mediated damage of myelin sheaths and the subsequent loss of mature oligodendrocytes are resulting in impaired axonal integrity,neurodegeneration and accounts for irreversible neuronal damage(Kuhlmann et al.,2023).The current landscape of available disease-modifying therapies comprises mainly immunomodulatory drugs that effectively diminish relapses and slow down progression at the onset form of the disease,namely relapsing MS(RMS).In this regard,a number of drugs have been approved as disease-modifying therapies for MS by US Food and Drug Administration and European Medicines Agencies(Box 1).

An integrated strategy of UPLC-Q-TOF/MS and HPTLC/PAD-DESI-MSI for the analysis of chemical variations:A case study of Tibetan medicine Tiebangchui

The dried roots of Aconitum pendulum Busch are the major source of a commonly used Tibetan medicine,namely Tiebangchui(TBC)(Fig.S1).However,raw TBC contains a large amount of high toxic diester-diterpenoid alkaloids(DDAs),and the improper use would cause arrhythmia,irreversible cardiovascular damages,and even death.“Paozhi”,an appropriate processing method,is the essential prerequisite for the safe clinical application of TBC.Water-decocting and sand-frying are commonly used processing methods for toxicity attenuation and efficacy preservation for TBC.

The Decarbonization of Construction—How Can Alkali-Activated Materials Contribute?

1.Introduction and context Enormous emphasis is currently being paid to the decarbonization of the global built environment as a leading priority for the engineering community and related industrial sectors[1].One of the main contributors to the overall emissions footprint of the built environment-and thus a cornerstone of efforts to achieve decarbonization-is the emissions profile of construction materials during their production and utilization.The cement and concrete sector is the largest-volume contributor to the emissions incurred in meeting the world’s construction material needs and is therefore targeted in the discussion of the deep,rapid decarbonization that must be achieved in order to minimize irreversible damage to the Earth and its ecosystems.

Apolipoprotein A-I binding protein-mediated neuroprotection in glaucomatous neuroinflammation and neurodegeneration

Glaucoma is a multifactorial eye disorder that can cause vision loss and irreversible blindness,affecting individ uals aged 40 to 80 yea rs worldwide.Due to the aging population,it is expected that the number of people affected by glaucoma will surpass 111 million by 2040 as the disease becomes more prevalent.Glaucoma primarily contributes to optic nerve axon loss and the progressive degeneration of retinal ganglion cells (RGCs),subsequently leading to vision impairment.

A-kinase anchoring protein-mediated compartmentalization of pro-survival signaling in the retina

The retina plays a fundamental role in the process of vision,serving as the primary interface between external visual stimuli and the central nervous system.Because the retina is exposed to a variety of environmental stresses and deleterious insults,it is susceptible to a spectrum of pathological conditions that can detrimentally affect vision.This often leads to irreversible vision loss due to the injury of specific cell types.For instance,inherited retinal degeneration and age-related macular degeneration can lead to the death of photoreceptors,while conditions like glaucoma and optic nerve injury can result in the loss of ganglion cells.The precise pathological mechanisms driving retinal degeneration remain largely elusive,although research utilizing mouse models suggests that disruptions in intracellular signal transduction pathways may play a pivotal role.Signaling pathways within the retina orchestrate various aspects of retinal physiology,including phototransduction,synaptic transmission,and neuronal survival.

Enhancing the vertical resolution of lunar penetrating radar data using predictive deconvolution

The Yutu-2 rover onboard the Chang’E-4 mission performed the first lunar penetrating radar detection on the farside of the Moon.The high-frequency channel presented us with many unprecedented details of the subsurface structures within a depth of approximately 50 m.However,it was still difficult to identify finer layers from the cluttered reflections and scattering waves.We applied deconvolution to improve the vertical resolution of the radar profile by extending the limited bandwidth associated with the emissive radar pulse.To overcome the challenges arising from the mixed-phase wavelets and the problematic amplification of noise,we performed predictive deconvolution to remove the minimum-phase components from the Chang’E-4 dataset,followed by a comprehensive phase rotation to rectify phase anomalies in the radar image.Subsequently,we implemented irreversible migration filtering to mitigate the noise and diminutive clutter echoes amplified by deconvolution.The processed data showed evident enhancement of the vertical resolution with a widened bandwidth in the frequency domain and better signal clarity in the time domain,providing us with more undisputed details of subsurface structures near the Chang’E-4 landing site.

Senolystics from natural products for extending health and lifespan

Senescence,a multifaceted cellular process,intricately regulates organismal aging by imposing irreversible growth arrest on cells.This phenomenon,characterized by altered gene expression and the accumulation of senescent cells,significantly contributes to age-related physiological decline and the onset of various age-associated pathologies[1].Cellular senescence,the irreversible cessation of cell division,is intricately linked to the aging process in individuals[2].As organisms age,the accumulation of senescent cells increases,contributing to tissue dysfunction and the development of age-related pathologies.Understanding the mechanisms underlying cellular senescence holds promise for elucidating the fundamental processes governing aging and may pave the way for targeted interventions to mitigate age-associated decline[3].

Epigenetic modification of the Wnt signaling pathway:a potential target for intestinal aging

Intestinal aging is emerging as a major public health problem The world has entered an aging society,and it is expected that the global population aged 60 years or older will reach 1.5 billion by 2035[1].Aging is gradually becoming a major public health issue,posing a significant challenge to healthcare systems[2].It is a complex natural physiological process involving the irreversible degeneration of body cells,tissues,and organs,and it is a major risk factor for many chronic diseases.

Sounding Board. The illness as the focus of geriatric medicine

Understanding the difference between illness and disease is a prerequisite to the care of patients affected by incurable disorders.Educated palliation in the absence of substantive information regarding this discrepancy is the art of medicine.Because elderly patients often present with several chronic diseases,many of which are irreversible,cure-oriented physicians caring for the elderly are especially vulnerable to frequent disappointments.

Thermomechanical Dynamics (TMD) and Bifurcation-Integration Solutions in Nonlinear Differential Equations with Time-Dependent Coefficients

The new independent solutions of the nonlinear differential equation with time-dependent coefficients (NDE-TC) are discussed, for the first time, by employing experimental device called a drinking bird whose simple back-and-forth motion develops into water drinking motion. The solution to a drinking bird equation of motion manifests itself the transition from thermodynamic equilibrium to nonequilibrium irreversible states. The independent solution signifying a nonequilibrium thermal state seems to be constructed as if two independent bifurcation solutions are synthesized, and so, the solution is tentatively termed as the bifurcation-integration solution. The bifurcation-integration solution expresses the transition from mechanical and thermodynamic equilibrium to a nonequilibrium irreversible state, which is explicitly shown by the nonlinear differential equation with time-dependent coefficients (NDE-TC). The analysis established a new theoretical approach to nonequilibrium irreversible states, thermomechanical dynamics (TMD). The TMD method enables one to obtain thermodynamically consistent and time-dependent progresses of thermodynamic quantities, by employing the bifurcation-integration solutions of NDE-TC. We hope that the basic properties of bifurcation-integration solutions will be studied and investigated further in mathematics, physics, chemistry and nonlinear sciences in general.

Irreversible electroporation for the management of pancreatic cancer: Current data and future directions

Pancreatic cancer is currently the seventh leading cause of cancer death(4.5%of all cancer deaths)while 80%-90%of the patients suffer from unresectable disease at the time of diagnosis.Prognosis remains poor,with a mean survival up to 15 mo following systemic chemotherapy.Loco-regional thermal ablative techniques are rarely implemented due to the increased risk of thermal injury to the adjacent structures,which can lead to severe adverse events.Irreversible electroporation,a promising novel non-thermal ablative modality,has been recently introduced in clinical practice for the management of inoperable pancreatic cancer as a safer and more effective loco-regional treatment option.Experimental and initial clinical data are optimistic.This review will focus on the basic principles of IRE technology,currently available data,and future directions.

Practical evaluation of prelithiation strategies for next-generation lithium-ion batteries

With the increasing market demand for high-performance lithium-ion batteries with high-capacity electrode materials,reducing the irreversible capacity loss in the initial cycle and compensating for the active lithium loss during the cycling process are critical challenges.In recent years,various prelithiation strategies have been developed to overcome these issues.Since these approaches are carried out under a wide range of conditions,it is essential to evaluate their suitability for large-scale commercial applications.In this review,these strategies are categorized based on different battery assembling stages that they are implemented in,including active material synthesis,the slurry mixing process,electrode pretreatment,and battery fabrication.Furthermore,their advantages and disadvantages in commercial production are discussed from the perspective of thermodynamics and kinetics.This review aims to provide guidance for the future development of prelithiation strategies toward commercialization,which will potentially promote the practical application of next-generation high-energy-density lithium-ion batteries.

Oxygen-defects evolution to stimulate continuous capacity increase in Co-free Li-rich layered oxides

Though oxygen defects are associated with deteriorated structures and aggravated cycling performance in traditional layered cathodes,the role of oxygen defects is still ambiguous in Li-rich layered oxides due to the involvement of oxygen redox.Herein,a Co-free Li-rich layered oxide Li_(1.286)Ni_(0.071)Mn_(0.643)O_(2)has been prepared by a co-precipitation method to systematically investigate the undefined effects of the oxygen defects.A significant O_(2)release and the propagation of oxygen vacancies were detected by operando differential electrochemical mass spectroscopy(DEMS)and electron energy loss spectroscopy(EELS),respectively.Scanning transmission electron microscopy-high angle annular dark field(STEMHAADF)reveals the oxygen vacancies fusing to nanovoids and monitors a stepwise electrochemical activation process of the large Li_(2)MnO_(3)domain upon cycling.Combined with the quantitative analysis conducted by the energy dispersive spectrometer(EDS),existed nano-scale oxygen defects actually expose more surface to the electrolyte for facilitating the electrochemical activation and subsequently increasing available capacity.Overall,this work persuasively elucidates the function of oxygen defects on oxygen redox in Co-free Li-rich layered oxides.

The pathology behind glaucoma:what we already know using omics technologies

The term glaucoma encompasses a spectrum of eye diseases pathologically characterized by an irreversible loss of retinal ganglion cells and their associated axons. Patients initially suffer from gaps in their visual field, the part of the visual range that can be perceived without eye movement. In the early stages of the disease, this damage can be compensated very well by eye movements. This, in turn, means that glaucoma is often not diagnosed until the disease is more advanced.

Nociceptors are needed to guide tooth development,function,repair,and regeneration

Toothaches have received widespread attention and commentary dating back to ancient times,appearing in Egyptian texts from over 3000 years ago and the writings of Hippocrates,Aristotle,and Galen.Scientific studies of the innervation of dental pulp and dentin date back to at least the 1800’s,yet our understanding of the basis for tooth pain is still limited.Standard treatments for toothache continue to be drastic and irreversible,including removal of the dental pulp or extraction of the tooth.While the trigeminal sensory innervation of the tooth pulp is commonly the origin of toothache pain,it is also indispensable for normal function and physiology,and should be retained as an integral part of the repaired tooth.Repair or regeneration of the dental pulp and its innervation could represent the next step in restorative dentistry,but a better understanding of the roles of the tooth’s sensory nerve supply and the mechanisms underlying its development and repair is needed.

Oxidation of benzene to phenol with N_(2)O over a hierarchical Fe/ZSM-5 catalyst

Catalytic oxidation of benzene with N_(2)O to phenol over the hierarchical and microporous Fe/ZSM-5-based catalysts in a continuous fixedbed reactor was investigated.The spent catalyst was in-situ regenerated by an oxidative treatment using N_(2)O and in total 10 reaction-regeneration cycles were performed.A 100% N_(2)O conversion,93.3% phenol selectivity,and high initial phenol formation rate of 16.49±0.06mmol_(phenol gcatalyst)^(-1)h^(-1)at time on stream(TOS) of 5 min,and a good phenol productivity of 147.06 mmol_(phenol gcatalyst)^(-1)during catalyst lifetime of 1800 min were obtained on a fresh hierarchical Fe/ZSM-5-Hi2.8 catalyst.With the reaction-regeneration cycle,N_(2)O conversion is fully recovered within TOS of 3 h,moreover,the phenol productivity was decreased ca.2.2±0.8% after each cycle,leading to a total phenol productivity of ca.0.44 ton_(pheol kg_(catalyst)^(-1)estimated for 300 cycles.Catalyst characterizations imply that the coke is rapidly deposited on catalyst surface in the initial TOS of 3 h(0.28 mgc_(gcatalyst)^(-1)min^(-1)) and gradually becomes graphitic during the TOS of 30 h with a slow formation rate of 0.06 mgc g_(catalyst)^(-1)min^(-1).Among others(e.g.,the decrease of textural property and acidity),the nearly complete coverage of the active Fe-O-Al sites by coke accounts for the main catalyst deactivation.Besides these reversible deactivation characteristics related to coking,the irreversible catalyst deactivation is also observed with the reaction-regeneration cycle.The latter is reflected by a further decreased amount of the active Fe-O-Al sites,which agglomerate on catalyst surface with the cycle,likely associated with the hard coke residue that is not completely removed by the regeneration.

Experimental study on the irreversible displacement evolution and energy dissipation characteristics of disturbance instability of regular joints

To investigate the disturbance-induced shear instability mechanism of structural catastrophe in the deep rock mass,MTS 815 material testing machine was used to carry out quasi-static loading tests and disturbance shear tests on symmetrical regular dentate joints of two materials at three undulation angles under specific initial static stress,disturbance frequency,and peak value.The test results indicate that:(i)the total ultimate instability displacement is only related to the intrinsic properties of the joints but not to the initial static stress and disturbance parameters;(ii)the cumulative irreversible displacement required for the disturbance instability conforms to the logistic inverse function relationship with the number of disturbances,displaying the variation trend of“rapid increase in the front,stable in the middle,and sudden increase in the rear”;(iii)the accumulation of plastic deformation energy is consistent with the evolution law of irreversible displacement of joints and the overall proportion of hysteretic energy is not large;(iv)the dissipated energy required for the instability of each group of joints is basically the same under various disturbance conditions,and this energy is mainly controlled by the initial shear stress and has no connection with the disturbance parameters.The stability of the total disturbance deformation and the disturbance energy law of the joints revealed in the tests provide data support for reasonably determining the disturbance instability criterion of joints.

External-to-internal synergistic strategy to enable multi-scale stabilization of LiCoO_(2)at high-voltage

High-voltage LiCoO_(2)(LCO)offers a prelude to breaking the bottleneck of the energy density of lithium-ion batteries,however,LiCoO_(2)is subject to serious structural and interfacial degradation above voltages>4.55 V(vs.Li/Li^(+)).Herein,an in-situ Li_(6.25)La_(3)Zr_(2)A_(l0.25)O_(12)(LLZAO)layer is constructed on the LCO surface to achieve operating voltage at 4.6 V.The detailed characterizations(ex-situ XRD,ex-situ Raman,DFT,etc.)reveal that the LLZAO layer greatly enhances Li+conductivity attributed to the ionconducting layer on the surface/interface,and closely combines with LiCoO_(2)particle to ensure stable cathode/electrolyte interface,thus suppressing the highly reactive Co^(4+)and O^(-)triggered surface side reactions at high-voltage.Moreover,the introduction of La^(3+)/Zr^(4+)/Al^(3+)with a larger ionic radius(La^(3+)/Zr^(4+)are larger than Co^(3+))and weaker electronegativity(La/Zr/Al are weaker than Co)into Co^(3+)sites readjusts the electron cloud density between Co–O–Li,which reinforces the Co–O bond and widens the band-center gap of Co 3d and O 2p,thus restraining the detrimental phase transition(from H3 to H1-3 phase)and the formation of Co_(3)O_(4)spinel phase(attributed to lattice oxygen release),subsequently alleviating the particle cracking and structural collapse during repeated Li^(+)de/intercalation.Therefore,after 100 cycles at 3.0–4.6 V,LCO@1.0LLZAO exhibits a superior discharge capacity of 188.5 m A h g^(-1),with a capacity retention of 85.1%.The above research has brought about meaningful guidance for the evolution of cathode materials with high voltage.

Nanoparticle Targeting with Antibodies in the Central Nervous System

Treatments for disease in the central nervous system(CNS)are limited because of difficulties in agent penetration through the blood-brain barrier,achieving optimal dosing,and mitigating off-target effects.The prospect of precision medicine in CNS treatment suggests an opportunity for therapeutic nanotechnology,which offers tunability and adaptability to address specific diseases as well as targetability when combined with antibodies(Abs).Here,we review the strategies to attach Abs to nanoparticles(NPs),including conventional approaches of chemisorption and physisorption as well as attempts to combine irreversible Ab immobilization with controlled orientation.We also summarize trends that have been observed through studies of systemically delivered Ab–NP conjugates in animals.Finally,we discuss the future outlook for Ab–NPs to deliver therapeutics into the CNS.