Precessing jet nozzle connecting to a spinning black hole in M87.

The nearby radio galaxy M87 offers a unique opportunity to explore the connections between the central supermassive black hole and relativistic jets. Previous studies of the inner region of M87 revealed a wide opening angle for the jet originating near the black hole1-4. The Event Horizon Telescope resolved the central radio source and found an asymmetric ring structure consistent with expectations from general relativity5. With a baseline of 17 years of observations, there was a shift in the jet's transverse position, possibly arising from an 8- to 10-year quasi-periodicity3. However, the origin of this sideways shift remains unclear. Here we report an analysis of radio observations over 22 years that suggests a period of about 11 years for the variation in the position angle of the jet. We infer that we are seeing a spinning black hole that induces the Lense-Thirring precession of a misaligned accretion disk. Similar jet precession may commonly occur in other active galactic nuclei but has been challenging to detect owing to the small magnitude and long period of the variation.

Necroptosis inhibitors: mechanisms of action and therapeutic potential.

Necroptosis is a type of programmed cell death that is morphologically similar to necrosis. This type of cell death is involved in various pathophysiological disorders, including inflammatory, neurodegenerative, infectious, and malignant diseases. Receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like protein (MLKL) pseudokinase constitute the core components of the necroptosis signaling pathway and are considered the most promising targets for therapeutic intervention. The discovery and characterization of necroptosis inhibitors not only accelerate our understanding of the necroptosis signaling pathway but also provide important drug candidates for the treatment of necroptosis-related diseases. Here, we will review recent research progress on necroptosis inhibitors, mechanisms of action and their potential applications for disease treatment.

Advances in the synthesis of functionalized tetrahydropyridazines from hydrazones.

The tetrahydropyridazine motif is widely present in plenty of natural products and biologically active molecules. Easily prepared from the condensation of carbonyls with hydrazines, hydrazones are versatile synthetic building blocks that are frequently used in organic synthesis. Hydrazones are also utilized in the synthesis of nitrogen-containing molecules, especially nitrogen-containing heterocycles. The presence of the CN-N unit in the product makes hydrazones ideal substrates for the synthesis of tetrahydropyridazine derivatives. Here, in this review, we summarize the recent progress in the construction of variously substituted tetrahydropyridazines from different hydrazone derivatives together with mechanism discussions.

Organophotocatalytic pyridination of N-arylglycines with 4-cyanopyridines by decarboxylative and decyanative radical-radical coupling.

A photocatalytic decarboxylative aminoalkylation of 4-cyanopyridines with N-arylglycines is achieved, providing 4-(aminomethyl)pyridine derivatives in moderate to good yields. This organic photocatalytic reaction undergoes a radical-radical cross-coupling process under redox-neutral conditions, featuring simple operation, readily available N-arylglycines and a broad substrate scope. Mechanistic investigations indicated that a proton-coupled electron-transfer process was involved to enable the single electron transfer between the reduced photocatalyst and 4-cyanopyridine in the presence of N-arylglycines.

Metal-free polychloromethylation/cyclization of unactivated alkenes towards ring-fused tricyclic indolones and benzoimidazoles.

Polychloromethylative cyclization of N-alkenyl indoles was developed under metal-free conditions to afford tricyclic pyridoindolones and pyrroloindolones in moderate to good yields. In the reaction, commercially available CHCl3 and CH2Cl2 were employed as tri- and dichloromethyl radical sources. Moreover, tri- and dichloromethylated polycyclic benzoimidazoles can also be obtained under standard conditions.

Recent advances in C-H functionalization of 2H-indazoles.

2H-Indazoles are one class of the most important nitrogen-containing heterocyclic compounds. The 2H-indazole motif is widely present in bioactive natural products and drug molecules that exhibit distinctive bioactivities. Therefore, much attention has been paid to access diverse 2H-indazole derivatives. Among them, the late-stage functionalization of 2H-indazoles via C-H activation is recognized as an efficient approach for increasing the complexity and diversity of 2H-indazole derivatives. In this review, we summarized recent achievements in the late-stage functionalization of 2H-indazoles, including the C3-functionalization of 2H-indazoles through transition metal-catalyzed C-H activation or a radical pathway, transition metal-catalyzed ortho C2'-H functionalization of 2H-indazoles and remote C-H functionalization at the benzene ring in 2H-indazoles.

Metal-free polychloromethyl radical-initiated cyclization of unactivated N-allylindoles towards pyrrolo[1,2-a]indoles.

A metal-free polychloromethyl radical-initiated cyclization of unactivated alkenes was developed using CH2Cl2 and CHCl3 as the di- and trichloromethyl radical sources. Variously substituted N-allyl-indoles were successfully transformed into the corresponding C2-(di- and trichloromethyl) pyrrolo[1,2-a]indoles in moderate to good yields. This reaction has a broad substrate scope and good functional group tolerance. Dibromomethylated products can also be obtained using CH2Br2 under standard conditions.

Three-component synthesis of arylsulfonyl-substituted indolo[2,1-a]isoquinolinones and benzimidazo-[2,1-a]isoquinolin-6(5H)-ones by SO2 insertion and radical cascade cyclization.

An efficient arylsulfonylation/cyclization of 2-aryl-N-methacryloyl indoles with potassium metabisulfite and aryldiazonium tetrafluoroborates was developed. A series of variously substituted arylsulfonyl indolo[2,1-a]isoquinolin-6(5H)-ones were formed in moderate to good yields via utilization of the nature abundant inorganic salt potassium metabisulfite as a SO2 surrogate. Additionally, this three-component protocol can also be employed for the synthesis of arylsulfonyl-substituted benzimidazo-[2,1-a]isoquinolin-6(5H)-ones.

The effectiveness and safety of growth factors in the treatment of tympanic membrane perforations: a systematic review and meta-analysis of randomized controlled trials.

PURPOSE: To determine the clinical efficacy and safety of growth factors in the treatment of tympanic membrane (TM) perforations from randomized controlled trials (RCTs). METHODS: Databases, including PubMed, EMBASE, Cochrane library, Ebsco, Ovid, Scopus, and Web of Science, were searched for articles in any language about studies on the treatment of TM perforations with growth factors. Inclusion criteria were: (1) randomized controlled trials (RCTs); (2) only patients with TM perforations included; and (3) any kinds of growth factors or related products were used as an intervention. Exclusion criteria were: (1) study was not reported as a full paper, only as an abstract; (2) review studies and case reports; and (3) an inability to extract valid data. Outcomes of interest included perforation closure rate, closure time, hearing improvement, and complications. RESULTS: Nineteen RCTs with a total of 1335 participants were included. Growth factors effectively increased the rate of perforation closure [risk ratio (RR): 1.21 95% confidence interval (1.12, 1.30), p < 0.01] and shortened closure time [mean difference (MD): - 16.71 (- 22.74, - 10.15), p < 0.01]. There was no significant difference in hearing improvement [MD: 0.10 (- 0.50, 0.70), p = 0.74] or complications [RR: 1.49 (0.96, 2.32), p = 0.07] between the growth factor intervention group and the control group. CONCLUSION: Growth factors are effective and safe in the treatment of TM perforations. However, better designed clinical trials should be carried out in the future to obtain more robust findings about the effectiveness of growth factors in the treatment of TM perforations.

CX3CR1 deficiency aggravates brain white matter injury and affects expression of the CD36/15LO/NR4A1 signal.

OBJECTIVE: To study the effects of CX3CR1 on white matter injury, neurofunction, recognition, and expression of the CD36/15LO/NR4A1 signal in mice with traumatic brain injury (TBI). METHODS: CX3CR1GFP/GFP, CX3CR1GFP/+ and C57BL/6 male mice were randomly divided into 3 groups. We used a controlled cortical impact (CCI) to establish a TBI model and T2wt MRI to detect the TBI lesion. FA and DTI allowed for quantitative evaluation of the structural integrity of white matter tracts. Several behavior tests were used to investigate nerve function; a computer-based tracing system was used to trace and analyze dendrites and cell bodies of microglia and astrocytes in the peri-lesional brain areas. We also used RT-PCR and western blot to detect the effect of CX3CL1/CX3CR1 axis on CD36/15LO/NR4A1 signal. RESULTS: The fractional anisotropy (FA) at the corpus callosum area of brain was decreased at 3 days post TBI, the average lesion volume CX3CR1GFP/GFP group was increased, and the neurologic deficit scores of mice of Cx3Cr1GFP/+ and wild-type groups were significantly increased compared to Cx3Cr1GFP/GFP group mice. In the Corner turn test, TBI induced impairments in forelimb function that were more severe than Cx3Cr11GFP/+ and wild-type TBI mice. We operated the Y-maze at 3 days post-TBI and the NOR test at 28 days after TBI. There was a significant TBI effect induced in decreased percentage entries into the novel arm in Cx3Cr1GFP/+ and wild-type TBI mice, compared with Cx3Cr1GFP/GFP; Cx3Cr1GFP/+. Wild-type mice showed decreased exploration time in new objects compared with Cx3Cr1GFP/GFP. Those two behavior tests demonstrated that Cx3Cr1 knock-out increased the damage caused by TBI to memory. In the tail suspension and force swimming tests, there was no significant difference between those three groups. CD36 increased in Cx3Cr1GFP/GFP compared with the other three groups at 3 days after TBI. TBI inhibited the expression of NR4A1 at 3 d after damage. Cx3Cr1 deficiency can induce high expression of 15LO, this was unaffected by TBI. CONCLUSION: CX3CR1 deletion can enhance white matter injury. It increased the expression of CD36 and 15LO and increased expression of NR4A1. The lack of CX3CR1 can affect the recovery of nerve function.

RhIII -Catalyzed C6-Selective Oxidative C-H/C-H Crosscoupling of 2-Pyridones with Thiophenes.

A rhodium(III)-catalyzed C6-selective dehydrogenative cross-coupling of 2-pyridones with thiophenes was developed for the synthesis of 6-thiophenyl pyridin-2(1H)-one derivatives. In this reaction, the excellent site selectivity was controlled by the 2-pyridyl directing group on the nitrogen of the pyridone ring. Control experiments indicated that the N-pyridyl was essential for the transformation. To the best of our knowledge, this procedure is the first successful example of the direct C6 heteroarylation of 2-pyridones with electron-rich thiophene derivatives. 4-Pyridone was also used as substrate to generate the corresponding C2 heteroarylated product. Moreover, this pyridyl directing group was readily removable to generate the biheteroaryl structures with a free N-H group.

Recent advances in rhodium-catalyzed C(sp2)-H (hetero)arylation.

Arylation is a common behaviour in organic synthesis for the construction of complex structures, especially the biaryls. Among those reported arylation procedures, transition-metal-catalyzed direct C(sp2)-H arylation has been rapidly developed in recent decades and has become a reliable alternative to traditional cross-coupling procedures using organometallic reagents. Great achievements in rhodium-catalyzed C(sp2)-H arylation have been witnessed during the last decade. Aryl halides, simple arenes, aryl boronic acids, arylsilanes, aryl aldehyde, aryl carboxylic acid, diazides, etc. were successfully utilized as arylating reagents under rhodium-catalyzed conditions. In this review, recent achievements in rhodium-catalyzed arylations through C(sp2)-H bond activation were summarized together with the mechanism discussions.

Peroxide-mediated synthesis of benzimidazo[2,1-a]isoquinoline-6(5H)-ones via cascade methylation/ethylation and intramolecular cyclization.

A metal-free oxidative radical methylation/arylation of 2-arylbenzoimidazoles with DTBP as the oxidant and methyl radical source was developed. The reaction proceeds through a sequential methyl radical addition/cyclization pathway and affords a series of methyl functionalized benzimidazo[2,1-a]isoquinoline-6(5H)-ones in moderate to good yields. Besides, the ethylation/arylation of 2-arylbenzoimidazoles was also achieved with DTAP.

DTBP-promoted site-selective α-alkoxyl C-H functionalization of alkyl esters: synthesis of 2-alkyl ester substituted chromanones.

The direct C-H functionalization of ethyl acetates was developed, delivering a variety of 1-(4-oxochroman-2-yl)ethyl acetate derivatives by reacting with chromones. This reaction has a wide substrate scope with excellent site-selective C-H activation at the inactive α-hydrogen of the alkoxyl group instead of the α-hydrogen of the carbonyl group under radical conditions. Compared with other protocols for the α-alkoxyl C-H functionalization of alkyl esters, a distinguishing feature of this reaction is that no metal catalyst was required, with DTBP as the sole oxidant.

Rhodium-catalyzed C-H activation/cyclization of aryl sulfoximines with iodonium ylides towards polycyclic 1,2-benzothiazines.

The synthesis of 1,2-benzothiazine derivatives through rhodium-catalyzed C-H activation/cyclization of S-aryl sulfoximines with iodonium ylides was developed for the first time. In this report, C-H and N-H bond functionalization was realized towards a series of tricyclic and tetracyclic sulfoximine derivatives with moderate to excellent yields under simple reaction conditions.

Can auditory brain stem response accurately reflect the cochlear function?

Auditory brain stem response (ABR) and compound action potential (CAP) recordings have been used in animal research to determine hearing sensitivity. Because of the relative ease of testing, the ABR test has been more commonly used in assessing cochlear lesions than the CAP test. The purpose of this experiment is to examine the difference between these two methods in monitoring the dynamic changes in auditory function after cochlear damage and in detecting asymmetric hearing loss due to unilateral cochlear damage. ABR and CAP were measured in two models of cochlear damage: acoustic trauma induced by exposure to a narrowband noise centered at 4 kHz (2,800-5,600 Hz) at 105 dB sound pressure level for 5 h in chinchillas and unilateral cochlear damage induced by surgical destruction of one cochlea in guinea pigs. Cochlear hair cells were quantified after completing the evoked potential testing. In the noise-damaged model, we found different recovery patterns between ABR and CAP. At 1 day after noise exposure, the ABR and CAP assessment revealed a similar level of threshold shifts. However, at 30 days after noise exposure, ABR thresholds displayed an average of 20-dB recovery, whereas CAP thresholds showed no recovery. Notably, the CAP threshold signifies the actual condition of sensory cell pathogenesis in the cochlea because sensory cell death is known to be irreversible in mammals. After unilateral cochlear damage, we found that both CAP and ABR were affected by cross-hearing when testing the damaged ear with the testing stimuli delivered directly into the canal of the damaged ear. When cross-hearing occurred, ABR testing was not able to reveal the presence of cross-hearing because the ABR waveform generated by cross-stimulation was indistinguishable from that generated by the test ear (damaged ear), should the test ear be intact. However, CAP testing can provide a warning sign, since the typical CAP waveform became an ABR-like waveform when cross-hearing occurred. Our study demonstrates two advantages of the CAP test over the ABR test in assessing cochlear lesions: contributing evidence for the occurrence of cross-hearing when subjects have asymmetric hearing loss and providing a better assessment of the progression of cochlear pathogenesis.NEW & NOTEWORTHY Auditory brain stem response (ABR) is more commonly used to evaluate cochlear lesions than cochlear compound action potential (CAP). In a noise-induced cochlear damage model, we found that the reduced CAP and enhanced ABR caused the threshold difference. In a unilateral cochlear destruction model, a shadow curve of the ABR from the contralateral healthy ear masked the hearing loss in the destroyed ear.

Alkylarylation of N-allylbenzamides and N-allylanilines with simple ethers for the direct construction of ether substituted dihydroisoquinolinones and indolines.

A radical-initiated cascade addition and cyclization of N-allylbenzamides with simple ethers to construct ether-substituted dihydroisoquinolinones was performed in the presence of CuI. The cleavage of the sp3 C-H bond in ether and the sp2 C-H bond in phenyl was involved in this reaction. Moreover, the arylalkylation of N-allylanilines was also realized under similar reaction conditions, providing ether-functionalized indolines in good to moderate yields.

Rh(iii)-Catalyzed regioselective C4 alkylation of indoles with allylic alcohols: direct access to ß-indolyl ketones.

A Rh(iii)-catalyzed and weak coordination carbonyl guided direct C4 alkylation of indoles with allylic alcohols was developed with excellent regioselectivity. This reaction was conducted under mild conditions, leading to a variety of ß-indolyl ketones with good functional group tolerance in moderate to good yields.

The Silver-Promoted Phosphonation/Alkynylation of Alkene Proceeding with Radical 1,2-Alkynyl Migration.

The silver-promoted phosphonation/alkynylation of vinyl in α-aryl α-alkynyl allylic alcohols with phosphine oxide was developed, affording a series of α-alkynyl γ-ketophosphine oxides in moderate to good yields. This procedure involved the radical 3-exo-dig cyclization, proceeding with the radical 1,2-alkynyl migration rather than the aryl migration.

Copper-Catalyzed Cascade Denitrogenative Transannulation/Hydrolyzation of 3-Aminoindazoles toward 2,2-Disubstituted Indanones.

A copper-catalyzed cascade denitrogenative transannulation/hydrolyzation of 3-aminoindazoles with N-(2-methylallyl)anilines was developed, affording a variety of 2-(aminomethyl)-2-methyl-indanones in moderate to good yields. 2-Cyanophenyl radical, which generated from oxidative denitrogenation of 3-aminoindazole, was proved as the reaction intermediate. This reaction features, along with the ready availability of starting materials, a cascade cleavage of two C-N bonds and construction of two C-C bonds in one pot.