Acid-sensing ion channel 1a:a novel target in Alzheimer's disease?

Alzheimer's disease(AD)represents the most common form of dementia and is characterized by a progressive decline of cognitive functions.Complex multifactorial processes underlie AD pathophysiology,including amyloid-beta(Aβ)toxicity,tau protein hyperphosphorylation,syna ptic dysfunction,oxidative stress,and neuroinflammation(J u and Tam,2022).

Investigational treatments for neurodegenerative diseases caused by inheritance of gene mutations:lessons from recent clinical trials

We reviewed recent major clinical trials with investigational drugs for the treatment of subjects with neurodegenerative diseases caused by inheritance of gene mutations or associated with genetic risk factors.Specifically,we discussed randomized clinical trials in subjects with Alzheimer's disease,Huntington's disease and amyotrophic lateral sclerosis bearing pathogenic gene mutations,and glucocerebrosidase-associated Parkinson's disease.Learning potential lessons to improve future therapeutic approaches is the aim of this review.Two long-term,controlled trials on three anti-β-amyloid monoclonal antibodies(solanezumab,gantenerumab and crenezumab)in subjects carrying Alzheimer's disease-linked mutated genes encoding for amyloid precursor protein or presenilin 1 or presenilin 2 failed to show cognitive or functional benefits.A major trial on tominersen,an antisense oligonucleotide designed to reduce the production of the huntingtin protein in subjects with Huntington's disease,was prematurely interrupted because the drug failed to show higher efficacy than placebo and,at highest doses,led to worsened outcomes.A 28-week trial of tofersen,an antisense oligonucleotide for superoxide dismutase 1 in patients with amyotrophic lateral sclerosis with superoxide dismutase 1 gene mutations failed to show significant beneficial effects but the 1-year open label extension of this study indicated better clinical and functional outcomes in the group with early tofersen therapy.A trial of venglustat,a potent and brain-penetrant glucosylceramide synthase inhibitor,in Parkinson's disease subjects with heterozygous glucocerebrosidase gene mutations revealed worsened clinical and cognitive performance of patients on the enzyme inhibitor compared to placebo.We concluded that clinical trials in neurodegenerative diseases with a genetic basis should test monoclonal antibodies,antisense oligonucleotides or gene editing directed against the mutated enzyme or the mutated substrate without dramatically affecting physiological wild-type variants.

Impairment of the nerve growth factor pathway driving amyloid accumulation in cholinergic neurons the incipit of the Alzheimer's disease story?

The current idea behind brain pathology is that disease is initiated by mild disturbances of common physiological processes. Overtime, the disruption of the neuronal homeostasis will determine irreversible degeneration and neuronal apoptosis. This could be also true in the case of nerve growth factor （NGF） al- terations in sporadic Alzheimer＇s disease （AD）, an age-related pathology characterized by cholinergic loss, amyloid plaques and neurofibrillary tangles. In fact, the pathway activated by NGF, a key neurotrophin for the metabolism of basal forebrain cholinergic neurons （BFCN）, is one of the first homeostatic systems affected in prodromal AD. NGF signaling dysfunctions have been thought for decades to occur in AD late stages, as a mere consequence of amyloid-driven disruption of the retrograde axonal transport of neuro- trophins to BFCN. Nowadays, a wealth of knowledge is potentially opening a new scenario： NGF signaling impairment occurs at the onset of AD and correlates better than amyloid load with cognitive decline. The recent acceleration in the characterization of anatomical, functional and molecular profiles of early AD is aimed at maximizing the efficacy of existing treatments and setting novel therapies. Accordingly, the elucidation of the molecular events underlying APP metabolism regulation by the NGF pathway in the sep- to-hippocampal system is crucial for the identification of new target molecules to slow and eventually halt mild cognitive impairment （MCI） and its progression toward AD.

Tissue with high intelligence quotient Adipose-derived stem cells in neural regeneration

The aim of the present review is to highlight the possible neuroregenerative potential ol adipose-derived stem cells. The key property of stem cells is plasticity including self-renewal, multilineage differentiation, and migration, whereas the required property is transplantability. For a long time, embryonic stem cells were thought to be the only source of pluripotency, a dogma that has been challenged during the last decade. Today, an alternative option might be adipose-derived stem cells, as easily accessible, ethical and autologous cellular source. Recent knowledge of adipobiology increasingly recognizes that adipose tissue is the major endo- and paracrine organ of the human body. Likewise, numerous neuropetides, neurotrophic factors, neurotransmitters, hypothalamic and steroid hormones and their receptors are shared by adipose tissue and brain. Accordingly, the regenerative potential of neuroprotective factor-secreting adipose-derived stem cells is outlined. Whether the possible benefits of adipose stem cell-based therapy may be mediated via cell transdifferentiation and/or paracrine mechanisms remains to further be evaluated.

Aneuploidy in stem cells

Stem cells hold enormous promise for regenerative medicine as well as for engineering of model systems to study diseases and develop new drugs. The discovery of protocols that allow for generating induced pluripotent stem cells(IPSCs) from somatic cells has brought this promise steps closer to reality. However,as somatic cells might have accumulated various chromosomal abnormalities,including aneuploidies throughout their lives,the resulting IPSCs might no longer carry the perfect blueprint for the tissue to be generated,or worse,become at risk of adopting a malignant fate. In this review,we discuss the contribution of aneuploidy to healthy tissues and how aneuploidy can lead to disease. Furthermore,we review the differences between how somatic cells and stem cells respond to aneuploidy.

Semiconductor,molecular and hybrid systems for photoelectrochemical solar fuel production

The paper shortly reviews the basic direct approaches applied in searching for viable solutions to solar fuel production. These are generally distinguished in molecular and semiconductor(non-molecular)systems, however, hybrid strategies, proposed recently, have also been included. The most promising efforts are considered, highlighting key aspects and emerging critical issues. Special attention is paid to aspects such as electrode architecture, device design, and main differences in the scientific vision and challenges to directly produce solar fuels. This overview could be useful to orientate the readers in the wide panorama of research activities concerning water splitting, natural and artificial photosynthesis, and solar fuel production through the identification of common aspects, specialties and potentialities of the many initiatives and approaches that are developing worldwide in this field with the final aim to meet world energy demand.

The energy-chemistry nexus: A vision of the future from sustainability perspective

The changing energy-chemistry nexus is discussed in this perspective paper about the future of sustainable energy and chemical production to identify the priorities and open issues on which focus research and development. Topics discussed regard （i） the new sustainable energy scenario, （ii） the role of energy storage （from smart grids to chemical storage of energy）, （iii） the outlooks and role of solar （bio）refineries and solar fuels, （iv） how to integrate hio- and solar-refineries to move to new economy, （v） the role of methanol at the crossover of new energy-chemistry nexus, （vi） the role of chemistry in this new scenario, （vii） the role of nanomaterials for a sustainable energy, （viii） the use of nanocarbons to design advanced energy conversion and storage devices, and （ix） possibilities and routes to exploit solar energy and methane （shale gas）. The contribution provides a glimpse of the emerging directions and routes with some elements about their possible role in the future scenario, but does not orovide a detailed analysis of the state of the art in these directions

Bio-inspired carbon electro-catalysts for the oxygen reduction reaction

We report the synthesis, characterisation and catalytic performance of two nature-inspired biomassderived electro-catalysts for the oxygen reduction reaction in fuel cells. The catalysts were prepared via pyrolysis of a real food waste（lobster shells） or by mimicking the composition of lobster shells using chitin and CaCO3 particles followed by acid washing. The simplified model of artificial lobster was prepared for better reproducibility. The calcium carbonate in both samples acts as a pore agent, creating increased surface area and pore volume, though considerably higher in artificial lobster samples due to the better homogeneity of the components. Various characterisation techniques revealed the presence of a considerable amount of hydroxyapatite left in the real lobster samples after acid washing and a low content of carbon（23%）, nitrogen and sulphur（〈1%）, limiting the surface area to 23 m^2/g, and consequently resulting in rather poor catalytic activity. However, artificial lobster samples, with a surface area of ≈200 m^2/g and a nitrogen doping of 2%, showed a promising onset potential, very similar to a commercially available platinum catalyst, with better methanol tolerance, though with lower stability in long time testing over 10,000 s.

COVID-19 and the gastrointestinal tract:Source of infection or merely a target of the inflammatory process following SARS-CoV-2 infection?

Gastrointestinal(GI)symptoms have been described in a conspicuous percentage of coronavirus disease 2019(COVID-19)patients.This clinical evidence is supported by the detection of viral RNA in stool,which also supports the hypothesis of a possible fecal-oral transmission route.The involvement of GI tract in severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection is corroborated by the theoretical assumption that angiotensin converting enzyme 2,which is a SARS-CoV-2 target receptor,is present along the GI tract.Studies have pointed out that gut dysbiosis may occur in COVID-19 patients,with a possible correlation with disease severity and with complications such as multisystem inflammatory syndrome in children.However,the question to be addressed is whether dysbiosis is a consequence or a contributing cause of SARS-CoV-2 infection.In such a scenario,pharmacological therapies aimed at decreasing GI permeability may be beneficial for COVID-19 patients.Considering the possibility of a fecal-oral transmission route,water and environmental sanitation play a crucial role for COVID-19 containment,especially in developing countries.

A long story for a short peptide:therapeutic efficacy of a cleavagespecific tau antibody

Tau is the prime participant in the Alzheimer’s disease(AD) neurodegeneration:AD,the main cause of dementia in elderly people,is a multifactorial neurodegenerative disorder characterized by a long prodromal phase(starting more than two decades before clinical symptoms appear)with brain accumulation/misfolding of amyloidβ(Aβ)in insoluble amyloid plaques and of tau protein in neurofibrillary tangles.

Adjustment of EU Neighborhood Policy:From Value-Driven to Interest-Oriented

As security in its neighborhood deteriorates,EU is making major adjustment to its Neighborhood Policy.The new policies are no longer value-driven,transformation-targeted,and single-handed,but more interest-oriented,flexible,differentiated and stability-targeted.The mode has been shifted from proactive export of democratic values,to reactive defense and

Interfacial potassium induced enhanced Raman spectroscopy for single-crystal TiO2 nanowhisker

Structural control and element doping are two popular strategies to produce semiconductors with surface enhanced Raman spectroscopy(SERS)properties.For TiO2 based SERS substrates,maintaining a good crystallinity is critical to achieve excellent Raman scattering.At elevated temperatures(N600°C),the phase transition from anatase to rutile TiO2 could result in a poor SERS performance.In this work,we report the successful synthesis of TiO2 nanowhiskers with excellent SERS properties.The enhancement factor,an index of SERS performance,is 4.96×106 for methylene blue molecule detecting,with a detection sensitivity around 10-7 mol·L-1.Characterizations,such as XRD,Raman,TEM,UV–vis and Zeta potential measurement,have been performed to decrypt structural and chemical characteristics of the newly synthesized TiO2 nanowhiskers.The photo absorption onset of MB adsorbed TiO2 nanowhiskers was similar to that of bare TiO2 nanowhiskers.In addition,no new band was observed from the UV–vis of MB modified TiO2 nanowhiskers.Both results suggest that the high enhancement factor cannot be explained by the charge-transfer mechanism.With the support of ab initio density functional theory calculations,we reveal that interfacial potassium is critical to maintain thermal stability of the anatase phase up to 900°C.In addition,the deposition of potassium results in a negatively charged TiO2 nanowhisker surface,which favors specific adsorption of methylene blue molecules and significantly improves SERS performance via the electrostatic adsorption effect.

小胶质细胞控制成年小鼠海马中的谷氨酸能突触

小胶质细胞是调节大脑突触发育和可塑性的重要细胞类型,但其影响突触的正常功能的机制尚不清楚。在本研究中,我们通过PLX5622造成小胶质细胞耗竭,并观察其对成年野生型小鼠海马CA3-CA1突触的影响。在小胶质细胞耗竭后,与树突棘密度降低相关的自发和诱发谷氨酸能活动的减少,出现未成熟突触特征以及突触的可塑性提高。小胶质细胞耗竭的小鼠在新物体识别任务的获取方面表现出缺陷。海马星形胶质细胞出现增生,但并没有神经炎症反应。在Cx3cr1-/-小鼠中,PLX不能导致海马出现上述改变。这说明CX3CL1/CX3CR1轴在小胶质细胞对突触功能的控制中有重要作用。PLX5622停用后,小胶质细胞的重新增殖,海马突触恢复,小鼠的学习功能也出现恢复。综上所述,小胶质细胞对维持成人大脑的突触的正常功能用重要的作用,去除小胶质细胞会导致谷氨酸能突触组织和活动的可逆变化。

Production of renewable fuels by blending bio-oil with alcohols and upgrading under supercritical conditions

The work studied a non-catalytic upgrading of fast pyrolysis bio-oil by blending under supercritical conditions using methanol,ethanol and isopropanol as solvent and hydrogen donor.Characterisation of the bio-oil and the upgraded bio-oils was carried out including moisture content,elemental content,pH,heating value,gas chromatography-mass spectrometry(GCMS),Fourier transform infrared radiation,13C nuclear magnetic resonance spectroscopy,and thermogravimetric analysis to evaluate the effects of blending and supercritical reactions.The GCMS analysis indicated that the supercritical methanol reaction removed the acids in the bio-oil consequently the pH increased from 2.39 in the crude bio-oil to 4.04 after the supercritical methanol reaction.The ester contents increased by 87.49% after the supercritical methanol reaction indicating ester formation could be the major deacidification mechanism for reducing the acidity of the bio-oil and improving its pH value.Simply blending crude bio-oil with isopropanol was effective in increasing the C and H content,reducing the O content and increasing the heating value to 27.55 from 17.51 MJ·kg^-1 in the crude bio-oil.After the supercritical isopropanol reaction,the heating value o f the liquid product slightly further increased to 28.85 MJ·kg^-1.

Constipation,deficit in colon contractions and alpha-synuclein inclusions within the colon precede motor abnormalities and neurodegeneration in the central nervous system in a mouse model of alphasynucleinopathy

Background:Gastrointestinal dysfunction can affect Parkinson’s disease(PD)patients long before the onset of motor symptoms.However,little is known about the relationship between gastrointestinal abnormalities and the development of PD.Contrary to other animal models,the human A53T alpha-synuclein(αS)transgenic mice,Line G2–3,developsαS-driven neurological and motor impairments after 9 months of age,displaying a long presymptomatic phase free of central nervous system(CNS)dysfunction.Methods:To determine whether this line can be suitable to study constipation as it occurs in prodromal PD,gastrointestinal functionality was assessed in young mice through a multidisciplinary approach,based on behavioral and biochemical analysis combined with electrophysiological recordings of mouse intestinal preparations.Results:We found that the A53TαS mice display remarkable signs of gastrointestinal dysfunction that precede motor abnormalities andαS pathology in the CNS by at least 6 months.YoungαS mice show a drastic delay in food transit along the gastrointestinal tract,of almost 2 h in 3 months old mice that increased to more than 3 h at 6 months.Such impairment was associated with abnormal formation of stools that resulted in less abundant but longer pellets excreted,suggesting a deficit in the intestinal peristalsis.In agreement with this,electrically evoked contractions of the colon,but not of the ileum,showed a reduced motor response in both longitudinal and circular muscle layers inαS mice already at 3 months of age,that was mainly due to an impaired cholinergic transmission of the underlying enteric nervous system.Interestingly,the presence of insoluble and aggregatedαS was found in enteric neurons in both myenteric and submucosal plexi only in the colon of 3 months oldαS mice,but not in the small intestine,and exacerbated with age,mimicking the increase in transit delay and the contraction deficit showed by behavioral and electrical recordings data.Conclusions:Gastrointestinal dysfunction in A53TαS mice represents an early sign ofαS-driven pathology without concomitant CNS involvement.We believe that this model can be very useful to study disease-modifying strategies that could extend the prodromal phase of PD and haltαS pathology from reaching the brain.

Experimental and theoretical study of microwave enhanced catalytic hydrodesulfurization of thiophene in a continuous-flow reactor

Hydrodesulfiirization(HDS)of thiophene,as a gasoline model oil,over an industrial Ni-Mo/Al2O3 catalyst was investigated in a continuous system under microwave irradiation.The HDS efficiency was much higher(5%-14%)under microwave irradiation than conventional heating.It was proved that the reaction was enhanced by both microwave thermal and non-thermal effects.Microwave selective heating caused hot spots inside the catalyst,thus improved the reaction rate.From the analysis of the non-thermal effect,the molecular collisions were significantly increased under microwave irradiation.However,instead of being reduced,the apparent activation energy increased.This may be due to the microwave treatment hindering the adsorption though upright S-bind(η1)and enhancing the parallel adsorption(η5),both adsorptions were considered to favor to the direct desulfurization route and the hydrogenation route respectively.Therefore,the HDS process was considered to proceed along the hydrogenation route under microwave irradiation.

Preface to the CSCST-25 Special lssue

The Chinese Society of Chemical Science and Technology in the United Kingdom(CSCST)was established in 1994 in London by an elite group of Chinese chemists and chemical engineers in the UK with the main aim to promote interaction,network and collaboration among the Chinese academics,postdoctoral researchers and PhDs,but not limited to,in the United Kingdom(UK)higher education institutions and relevant industries.Since then,the CSCST community has continuously grown and further contributed to the various fields of Chemical Science,Engineering and Technology in the UK,as well as worldwide.

Observation of an α-synuclein liquid droplet state and its maturation into Lewy body-like assemblies

Misfoldedα-synudein is a major component of Lewy bodies,which are a hallmark of Parkinson's disease(PD).A large body of evidence shows thatα-synuclein can aggregate into amyloid fibrils,but the relationship between a-synuclein self-assembly and Lewy body formation remains unclear.Here,we show,both in vitro and in a Caenorhabditis elegans model of PD,thatα-synuclein undergoes liquid-liquid phase separation by forming a liquid droplet state,which converts into an amyloid-rich hydrogel with Lewy-body-like properties.This maturation process towards the amyloid state is delayed in the presence of model synaptic vesicles in vitro.Taken together,these results suggest that the formation of Lewy bodies may be linked to the arrested maturation ofα-synuclein condensates in the presence of lipids and other cellular components.

Analysis of mesoscale effects in high-shear granulation through a computational fluid dynamics-population balance coupled compartment model

There is a need for mesoscale resolution and coupling between flow-field information and the evolution of particle properties in high-shear granulation. We have developed a modelling framework that com- partmentalizes the high-shear granulation process based on relevant process parameters in time and space. The model comprises a coupled-flow-field and population-balance solver and is used to resolve and analyze the effects of mesoscales on the evolution of particle properties. A Diosna high-shear mixer was modelled with microcrystalline cellulose powder as the granulation material. An analysis of the flow-field solution and compartmentalization allows for a resolution of the stress and collision peak at the impeller blades. Different compartmentalizations showed the importance of resolving the impeller region, for aggregating systems and systems with breakage. An independent study investigated the time evolution of the flow field by changing the particle properties in three discrete steps that represent pow- der mixing, the initial granulation stage mixing and the late stage granular mixing. The results of the temporal resolution study show clear changes in collision behavior, especially from powder to granular mixing, which indicates the importance of resolving mesoscale phenomena in time and space.