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A cytokine storm, autoimmune features and dysfunctions of myeloid cells significantly contribute to severe coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Genetic background of the host seems to be partly responsible for severe phenotype and genes related to innate immune response seem critical host determinants. The C9orf72 gene has a role in vesicular trafficking, autophagy regulation and lysosome functions, is highly expressed in myeloid cells and is involved in immune functions, regulating the lysosomal degradation of mediators of innate immunity. A large non-coding hexanucleotide repeat expansion (HRE) in this gene is the main genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), both characterized by neuroinflammation and high systemic levels of proinflammatory cytokines, while HREs of intermediate length, although rare, are more frequent in autoimmune disorders. C9orf72 full mutation results in haploinsufficiency and intermediate HREs seem to modulate gene expression as well and impair autophagy. Herein, we sought to explore whether intermediate HREs in C9orf72 may be a risk factor for severe COVID-19. Although we found intermediate HREs in only a small portion of 240 patients with severe COVID-19 pneumonia, the magnitude of risk for requiring non-invasive or mechanical ventilation conferred by harboring intermediate repeats &gt, 10 units in at least one C9orf72 allele was more than twice respect to having shorter expansions, when adjusted for age (odds ratio (OR) 2.36, 95% confidence interval (CI) 1.04–5.37, p = 0.040). The association between intermediate repeats &gt, 10 units and more severe clinical outcome (p = 0.025) was also validated in an independent cohort of 201 SARS-CoV-2 infected patients. These data suggest that C9orf72 HREs &gt, 10 units may influence the pathogenic process driving more severe COVID-19 phenotypes.

The Forkhead Box G1 (FOXG1) gene encodes a transcription factor with an essential role in mammalian telencephalon development. FOXG1-related disorders, caused by deletions, intragenic mutations or duplications, are usually associated with severe intellectual disability, autistic features, and, in 87% of subjects, epileptiform manifestations. In a subset of patients with FoxG1 mutations, seizures remain intractable, prompting the need for novel therapeutic options. To address this issue, we took advantage of a haploinsufficient animal model, the FoxG1 +/− mouse. In vivo electrophysiological analyses of FoxG1 +/− mice detected hippocampal hyperexcitability, which turned into overt seizures upon delivery of the proconvulsant kainic acid, as confirmed by behavioral observations. These alterations were associated with decreased expression of the chloride transporter KCC2. Next, we tested whether a triheptanoin-based anaplerotic diet could have an impact on the pathological phenotype of FoxG1 +/− mice. This manipulation abated altered neural activity and normalized enhanced susceptibility to proconvulsant-induced seizures, in addition to rescuing altered expression of KCC2 and increasing the levels of the GABA transporter vGAT. In conclusion, our data show that FoxG1 haploinsufficiency causes dysfunction of hippocampal circuits and increases the susceptibility to a proconvulsant insult, and that these alterations are rescued by triheptanoin dietary treatment.

Composites of polystyrene (PS) with cellulose microfibres and oat particles, obtained by melt mixing, were examined. The compatibilization of the composites was carried out by addition of maleic anhydride functionalized copolymers (SEBS-g-MA, PS-co-MA) and poly(ethylene glycol) to improve the fibre–matrix interfacial interactions. The plain components and their composites were characterised by FT-IR, DSC, TGA, SEM microscopy and mechanical tests. The properties of the various systems were analysed as a function of both fibre and compatibilizer amount. The compatibilized PS composites showed enhanced fibre dispersion and interfacial adhesion as a consequence of chemical interactions between the anhydride groups on the polymer chains and the hydroxyl groups on the fibres, as demonstrated by FT-IR spectroscopy. DSC analysis pointed out a neat increase of Tg of composites on addition of SEBS-g-MA, as compared to PS-co-MA. The thermal stability of composites was also influenced by the type and amount of fibres, as well as by the structure and concentration of compatibilizer. The effect of the reactive copolymers on the composites properties was accounted for on the basis of the polymer-polymer miscibility and chemical interactions at the matrix/filler interface.

An efficient and modulable total synthesis of discodermolide (DDM), a unique marine anticancer polyketide is described including relat- ed alternative synthetic approaches. Particularly notable is the repeated ap- plication of a crotyltitanation reaction to yield homoallylic (Z)-O-ene-carba- mate alcohols with excellent selectivity. Advantage was taken of this reaction not only for the stereocontrolled build- ing of the syn-anti methyl-hydroxy- methyl triads of DDM, but also for the direct construction of the terminal (Z)- diene. Of particular interest is also the installation of the C13=C14 (Z)-double bond through a highly selective dyo- tropic rearrangement. The preparation of the middle C8-C14 fragment in two sequential stages and its coupling to the C1-C7 moiety was a real challenge and required careful optimization. Sev- eral synthetic routes were explored to allow high and reliable yields. Due to the flexibility and robust character of this approach, it might enable a sys- tematic structural variation of DDM and, therefore, the elaboration and ex- ploration of novel discodermolide structural analogues.

Purpose To evaluate feasibility, diagnostic performance, patient acceptance, and overall examination time of CT colonography (CTC) performed through rectal administration of iodinated contrast material. Materials and methods Six-hundred asymptomatic subjects (male:female = 270:330; mean 63 years) undergoing CTC for colorectal cancer screening on an individual basis were consecutively enrolled in the study. Out of them, 503 patients (group 1) underwent CTC with rectal tagging, of which 55 had a total of 77 colonic lesions. The remaining 97 patients (group 2) were randomly selected to receive CTC with oral tagging of which 15 had a total of 20 colonic lesions. CTC findings were compared with optical colonoscopy, and per-segment image quality was visually assessed using a semi-quantitative score (1 = poor, 2 = adequate, 3 = excellent). In 70/600 patients (11.7%), CTC was performed twice with both types of tagging over a 5-year follow-up cancer screening program. In this subgroup, patient acceptance was rated via phone interview two weeks after CTC using a semi-quantitative scale (1 = poor, 2 = fair, 3 = average, 4 = good, 5 = excellent). Results Mean per-polyp sensitivity, specificity, positive and negative predictive values of CTC with rectal vs oral tagging were 96.1% (CI95% 85.4 ÷ 99.3%) vs 89.4% (CI95% 65.4 ÷ 98.1%), 95.3% (CI95% 90.7 ÷ 97.8%) vs 95.8% (CI95% 87.6 ÷ 98.9%), 86.0% (CI95% 73.6 ÷ 93.3) vs 85.0% (CI95% 61.1 ÷ 96.0%), and 98.8% (CI95% 95.3 ÷ 99.8%) vs 97.2% (CI95% 89.4 ÷ 99.5%), respectively (p > 0.05). Polyp detection rates were not statistically different between groups 1 and 2 (p > 0.05). Overall examination time was significantly shorter with rectal than with oral tagging (18.3 ± 3.5 vs 215.6 ± 10.3 minutes, respectively; p Conclusions Rectal iodine tagging can be an effective alternative to oral tagging for CTC with the advantages of greater patient acceptance and lower overall examination time.

A total synthesis of rhizoxin D (1b), a 16-membered antitumoral macrolide, is reported. The strategy relies on the application of a Brown allylation reaction for the C 15 and C 16 asymmetric centres control. Installation of the C17 hydroxyl function with concomitant building of the (E)-C18-C19 double bond was effected by a diastereoselective addition of vinyllithium derivative 15 to aldehyde 10. The terminal enone group was then introduced to achieve the preparation of C11-C20 segment 23. A Heck coupling reaction between C11-C20 fragment 23 and C3-C10 segment 24 (previously prepared in our laboratory) was performed with success to deliver the C3-C20 fragment 25. The total synthesis of rhizoxin D (1b) was achieved after transformation of 25 into the macrolactone 28, and coupling the C21-C28 side chain using a Wittig-Wadsworth-Emmons reaction.

A synthetic approach to the eastern part of spiramycin, an important antibiotic compound, is described. Introduction of the side chain was first envisaged through a Hoppe aldehyde allylation. This reaction was carried outbetween an optically pure aldehyde 32 and a (′)-γ-alkoxy allyltitanium(IV) species derived from a primary γ-alkoxy allyl (diisopropyl)carbamate. Under kinetic resolution conditions, the anti-Cram compound 35 was obtained in an 80:20 mixture, with the Cram isomer 34, in 81% yield. Employing the optically pure (S)-γ-alkoxy allyl (diisopropyl)carbamate 36, the corresponding (R)-γ-alkoxy allyltitanium (R)-'Ti'-III was generated under n-BuLi.TMEDA/Ti(Oi-Pr) 4 conditions, that reacted with aldehyde 32 in double stereodifferentiation to deliver the expected Cram compound 40 in 80% yield (95% de). This latter corresponded to the C1-C7 fragment of spiramycin.

An efficient access to optically active (R)- or (S)-γ-alkoxy allyltitanium(IV) intermediates, in aldehyde allylation reactions, is described. Enantiomeric γ-alkoxy secondary allyl carbamates (R)- and (S)-14 were first prepared. Determination of their enantiomeric excess was realised on the corresponding deuterated isotopic derivatives by NMR in chiral liquid media. Subsequent aldehyde allylation reaction with propanal performed under Hoppe n-BuLi.(-)-sparteine/Ti(Oi-Pr) 4 or n-BuLi.TMEDA/Ti(Oi-Pr) 4 conditions, led to both enantiomeric homoallylic alcohols 15 or ent-15 in 90% yield, 100% ed and 80% ee.

The synthesis of the S1-N10 nine-membered lactone core 28 of ent-griseoviridin is reported. Starting from cystine derivative 25, encompassing a terminal ynoate, treatment under Zn/ AcOH conditions led to the formation of lactone 28 in 12% yield. Therefore, the lactone moiety of ent-griseoviridin is obtained in 10.7% overall yield for two steps. An access to the corresponding 5-epi-griseoviridin lactone 29 is also described.

During the summer of 2001, 2-year-old Fraxinus excelsior and Fagus sylvatica plants were subjected to ozone-rich environmental conditions at the Regional Forest Nursery at Curno (Northern Italy). Atmospheric ozone concentrations and stomatal conductance were measured, in order to calculate the foliar fluxes by means of a one-dimensional model. The foliar structure of both species was examined (thickness of the lamina and of the individual tissues, leaf mass per area, leaf density) and chlorophyll a fluorescence was determined as a response parameter. Stomatal conductance was always greater in Fraxinus excelsior, as was ozone uptake, although the highest absorption peaks did not match the peaks of ozone concentration in the atmosphere. The foliar structure can help explain this phenomenon: Fraxinus excelsior has a thicker mesophyll than Fagus sylvatica (indicating a greater photosynthesis potential) and a reduced foliar density. This last parameter, related to the apoplastic fraction, suggests a greater ability to disseminate the gases within the leaf as well as a greater potential detoxifying capacity. As foliar symptoms spread, the parameters relating to chlorophyll a fluorescence also change. PI (Performance Index, Strasser, A., Srivastava, A., Tsimilli-Michael, M., 2000. The fluorescence transient as a tool to characterize and screen photosynthetic samples. In: Yunus, M., Pathre, U., Mohanty, P., (Eds.) Probing Photosynthesis: Mechanisms, Regulation and Adaptation. Taylor & Francis, London, UK, pp. 445-483.) has proved to be a more suitable index than Fv/Fm (Quantum Yield Efficiency) to record the onset of stress conditions.

International audience; A (Z)-vinyl (N,N-diisopropyl)carbamate treated with Grignard reagents, under Wenkert Nickel-catalyzed conditions, gave an access to several substituted (Z)-alkenyl derivatives. These Nickel-catalyzed reactions, carried out with vinyl-, phenyl-, p-methoxyphenyl-, trimethylsilylmethylmagnesium bromide and benzylmagnesium chloride, led to the corresponding (Z)-alkenyl derivatives in good yields and high stereoselectivities.

In our program of new macrocyclic antibiotic derivatives synthesis, a natural kijamicin analog was isolated, disclosing important antibiotic and antiviral properties, which are under investigation. In this paper we describe a synthesis of the bottom half C1-C14 ( n = 1) of its aglycon. This strategy was based on the preparation of a tetraene derivative via a palladium catalyzed Stille coupling reaction, the final step involving an IMDA cyclization key step.

International audience; Hydrazone 30, precursor of a taxoid C-ring, was synthesized in 7 steps from commercial 2-methyl-1,3-cyclohexanedione. An enantioselective approach to 30 was also investigated, using a reduction of diketone 11 with bakers' yeast to introduce enantioselectivity. During the alkyne isomerization step, anionic cyclizations of alkoxides and enolates onto the triple bond were observed, and a thorough study of these reactions is reported here. © Wiley-VCH Verlag GmbH, 2000.

International audience; Grubbs' and Schrock's catalysts can be used in ring-closing metathesis reactions (RCM) to synthesize highly functionalized cyclooctenes that have the required stereochemistry for the C1, C2, and C8 centers of taxol. The unprecedented formation of a trans isomer in the case of the carbonate derivative (see scheme) indicates that RCM does not always proceed to complete thermodynamic equilibrium.

The Hoppe reaction, which is an allylation reaction of aldehydes using an optically active titanated crotyl carbamate intermediate generated from the corresponding N,N-diisopropyl crotyl carbamate with n-BuLi/(−)-sparteine, was in most cases applied to achiral aldehydes. In this work an extension of this reaction is reported using a racemic γ-alkoxy allyltitanate (17) and an optically active aldehyde (16) to deliver in good yield the anti adduct 18 as the major isomer. When the corresponding δ-lactol 24 was used in place of aldehyde 16, the anti adduct 25 was obtained in 94% yield as the only product. Structural modifications effected on 25 delivered aldehyde 28 which was in turn submitted to a second allylation reaction in the presence of the optically active titanated crotyl carbamate 2, prepared as described by Hoppe from crotyl carbamate 1, to conduct to compound 29 in 80% yield. This derivative corresponds to a potential precursor of the C1−C9 portion of Tylonolide, aglycon of Tylosin (4).

Two different reactions were experimented for the construction of the eight-membered B-ring of taxane skeleton through the formation of the C9C10 bond. A SmI2 promoted radical reaction on seco-alkynyl aldehydes 11cis or 11trans failed. A Nozaki/Kishi reaction carried out on the seco-iodovinyl aldehyde 12trans led, through an unprecedented intramolecular SN2′ reaction, to the “abnormally” cyclised product 14, the structure of which has been confirmed by X-ray crystallography.

Different enynols and propargyl derivatives were sumitted to radical hydrostannylation (Bu3SnH/AIBN), Pd(0)-catalyzed hydrostannylation [Bu3SnH/Pd(0)], and stannylcupration [Bu3Sn(R)CuCNLi2] conditions. Except for the radical stannylation reaction, high regio- and stereoselective formation of vinyl- and dienylstannanes are obtained. Results are tentatively explained in terms of steric Interactions between the alkyne or enyne substituents and the palladium or cuprate moieties in the different reaction intermediates.

Stannylcupration of enyne 5 was performed with the homostannylcuprate (Bu 3 Sn) 2 CuCNLi 2 to deliver in a stereoselective way the distal dienylstannane 7 in 77% yield. This reaction was reproducible only when methanol was added to the cuprate solution. In comparison, hydroboration or hydrozirconation reactions failed in this case to produce the corresponding boron or zirconium derivative.

An approach of taxol synthesis based on the use of (E)-bis-1,2-(tributylstannyl)ethylene 6 as a readily available two-carbon 1,2-link between A and C-ring is described. The conjugate addition of a mixed higher-order stannylvinyl cyanocuprate derived from 6 on chiral cyclohexenone 5 is completely stereoselective. A model study on 3-methylcyclohex-2-enone showed that the afforded stannylvinyl cyclohexenone 12 can be engaged without further transformation in a Stille cross-coupling reaction with the vinyl triflate 4 corresponding to the A-ring of taxol to give seco-taxane 14.

Hemicalide is a novel marine metabolite polyketide distinguished by a unique mechanism of action. Because of insufficient quantities of purified material, this natural product has evaded complete stereochemical assignments. Recently, we have determined the relative stereochemistry of the C8-C13 hexad by synthesizing the C1-C13 fragment. Presently, we report the assignment of the C17-C25 δ-lactone fragment. NMR analysis of authentic hemicalide along with a computational conformation study allowed us to reduce the number of putative relative isomers from 16 to 4. Concise syntheses of the four candidate diastereomers were achieved using a common strategy based on a Dias aldehyde allylation reaction, an intramolecular Horner-Wadsworth-Emmons olefination, and a dihydroxylation reaction. Finally, thorough NMR comparisons enabled us to deduce the relative stereochemistry of the C1-C17 fragment with high certainty.

The allenyl titanium 11a, prepared using Yamamoto's conditions reacted with different aldehydes 12a-c to produce the anti acetylenic diols 13a-c. In a synthetic approach to erigerol 1 this reaction was applied to the aldehyde 4 and thr expected key intermediate 13d was obtained in 40% yield after removal of the THP group. During this study the α-alkoxypropargylstannane 14 and the α-alkoxyallenylstannane 15 were prepared in good yields after transmetallation of the corresponding lithio derivatives 5b and 7b by Ti(OiPr)4 or Et2ZnCl.

A highly diastereoselective synthesis of the taxane potential precursor 16 is achieved. An unexpected diastereoselectivity was observed upon condensation of the α-trimethylsilyloxyaldehydes 9a or 9b with the cyclohexenyllithium 10 . The single diol isomers 13A and 14A exhibiting the required 1β,2α relative configuration are obtained in good yields.

Metallate rearrangements were performed on α-(carbamoyloxy)alkenyl stannanes 4 in high yields to prepare (±)-8a and (±)-8b via alkyl transfer but failed when stannyl and stannylvinyl transfers were attempted to give 10ab and 1ab after quenching with Mel. After we optimized conditions on dihydrofuran 13, a model study, the dihydrofuran 19 could deliver cuprate rearrangements, leading after methylation to the stannyl derivative 10 and the stannyldiene 1 in good yields. A second approach for the synthesis of stannyldienes was envisaged via a Stille Pd(0) coupling reaction using (E)-1,2-bis(tributylstannyl)ethylene 11. An efficient method was performed by stannylcupration of the enyne (±)-24 which gave the expected stannyldiene (±)-1 in good yield and with high regio-and stereocontrols.

In a synthetic approach to forskolin 1 , a 6-endo-trig radical cyclisation was performed on propargylic derivative 12 to furnish in 60% yield compound 17 which contains the A-B ring system of forskolin. In the same way yn-one 14 submitted to Bu 3 SnH gave the expected cyclised product 19 in 55% yield. A particular 5-exo-dig cyclisation took place, leading to compound 18 in 10% yield, when silylated propargylic alcohol 13 was treated under the same conditions.

The synthesis of polyhydroxylated 6-N-benzylpiperidin-2-ones is described from the corresponding N-benzylaminoglycoside. These compounds are easily reduced to the differently protected 1, 5-dideoxy-1, 5-imino-D-xylitol.

From the dihydrofuran derivative 3, an mCPBA oxidation followed by an LAH reduction led to the 9β-hydroxy lactol 11, the Jones' oxidation of which gave the 9β-hydroxy lactone 13 together with the formyl ketone compound 7. Treatment of 13 with SOCl2-Py finally produced the Ziegler-Corey-Ikegami intermediate lactone 2 leading to a formal synthesis of (±)-forskoline.

International audience; An important feature of the synthesis of salinosporamide A, a potent proteasome inhibitor, is the establishment of the quaternary stereocenter at C3. A new route has been developed based on the methylation of a functionalized pyrrolidinone. Direct methylation reaction led to the unwanted diastereomer; however, by means of a Corey–Chaykovsky reaction followed by LiAlH4 epoxide opening, the desired alcohol was obtained. The pyrrolidinone was elaborated through a key allylation reaction between a tertiary allyltitanium reagent and an aldehyde bearing a spiroketal moiety in α-position

From available hydroxy-aldehyde 6 , propargylic derivative 8 was prepared and treated with Bu 3 SnH to give in 95% yield the bicyclic vinyl stannae 10 . After 10 was converted into the diol 15 , this latter was oxidated with the Dess-Martin reagent into the dialdehyde 4 . Compound 4 was then submitted to a pinacolic coupling reaction leading to the bicyclic cis-diol 3 in a stereospecific manner.

1,2-Metallate rearrangements were performed on α-(carbamoyl)alkenyl stannnane 6 with high yield in alkyl transfer to give 10 after quenching with MeI; disappointing results were obtained for preparation of 11 and 2b . Using dihydrofuran 13 , optimized conditions were found to realize 1,2-stannyl and 1,2-(stannyl)vinyl transfers, and methylation, leading to stannyl derivative 15 and stannyl diene 16 in good yields.

During cardiac angiography, hemodynamic alterations and surface electrocardiographic changes are common, predictable and dose-related adverse reactions to radiocontrast media. High osmolality, inadequate sodium content and local transient hypocalcemia are thought to be the main mechanisms responsible for these untoward cardiovascular effects. The purpose of this double-blind, parallel-group trial was to compare the hemodynamic and electrocardiographic responses to cardiac and selective coronary artery injection of iomeprol 400 (400 mgI/ml) and iopamidol 370 (370 mgI/ml). One-hundred consenting adult inpatients were randomised to receive iomeprol 400 (41 males, nine females; mean age, 56.6 years) or iopamidol 370 (46 males, four females; mean age, 57.6 years). Both agents produced minor and transient hemodynamic and electrophysiological effects. Following left ventriculography, iopamidol 370 produced a significantly greater increase in LVEDP than iomeprol 400 (mean increases after first and second left ventriculogram: 2.5 and 4.6 mmHg with iomeprol 400, 3.3 and 9.9 mmHg with iopamidol 370, P = 0.027). The QT-interval was more affected by iopamidol 370 than by iomeprol 400. However, post-contrast prolongation of the QT-interval was not significant with either agent, nor were there any significant T-wave, ST-segment or RR-interval changes associated with the injection of the test compounds. No serious adverse events occurred throughout the study. Mild pain was complained by only one patient, while most patients reported mild to moderate sensation of heat. Image quality of the vast majority of the procedures was rated as good or excellent in both patient groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Due to its intriguing biological activity profile and potential chemotherapeutic application discodermolide (DDM) proved to be an attractive target. Therefore, notable efforts have been carried out directed toward its total synthesis and toward the production and evaluation of synthetic analogues. Recently, we achieved the total synthesis of DDM. At the present, guided by the knowledge gained during our DDM total synthesis and by the requirement of keeping the bioactive "U" shape conformation, we report the convergent preparation of five original analogues. Three types of changes were realized through modification of the terminal (Z)-diene moiety, of the methyl group at the C14-position, and the lactone region. All analogues were active in the nanomolar range and two of them turned out to be equipotent to DDM.

From available hydroxy-aldehyde 6 , propargylic derivative 8 was prepared and treated with Bu 3 SnH to give in 95% yield the bicyclic vinyl stannae 10 . After 10 was converted into the diol 15 , this latter was oxidated with the Dess-Martin reagent into the dialdehyde 4 . Compound 4 was then submitted to a pinacolic coupling reaction leading to the bicyclic cis-diol 3 in a stereospecific manner.