Biological characterization of AB-343, a novel and potent SARS-CoV-2 M inhibitor with pan-coronavirus activity.

Since the SARS-CoV-2 outbreak, there have been ongoing efforts to identify antiviral molecules with broad coronavirus activity to combat COVID-19. SARS-CoV-2's main protease (M) is responsible for processing the viral polypeptide into non-structural proteins essential for replication. Here, we present the biological characterization of AB-343, a covalent small-molecule inhibitor of SARS-CoV-2 M with potent activity in both cell-based (EC = 0.

Rational Design of Macrocyclic Noncovalent Inhibitors of SARS-CoV-2 M from a DNA-Encoded Chemical Library Screening Hit That Demonstrate Potent Inhibition against Pan-Coronavirus Homologues and Nirmatrelvir-Resistant Variants.

The recent global COVID-19 pandemic has highlighted treatments for coronavirus infection as an unmet medical need. The main protease (M) has been an important target for the development of SARS-CoV-2 direct-acting antivirals. Nirmatrelvir as a covalent M inhibitor was the first such approved therapy.

Discovery of -Linked Nucleoside Analogues with Antiviral Activity against SARS-CoV-2.

The recent COVID-19 pandemic underscored the limitations of currently available direct-acting antiviral treatments against acute respiratory RNA-viral infections and stimulated major research initiatives targeting anticoronavirus agents. Two novel nsp5 protease (MPro) inhibitors have been approved, nirmatrelvir and ensitrelvir, along with two existing nucleos(t)ide analogues repurposed as nsp12 polymerase inhibitors, remdesivir and molnupiravir, but a need still exists for therapies with improved potency and systemic exposure with oral dosing, better metabolic stability, and reduced resistance and toxicity risks. Herein, we summarize our research toward identifying nsp12 inhibitors that led to nucleoside analogues and , which showed favorable pan-coronavirus activity in cell-infection screens, were metabolized to active triphosphate nucleotides in cell-incubation studies, and demonstrated target (nsp12) engagement in biochemical assays.

Reverse Genetics System for Rift Valley Fever Virus.

Rift Valley fever virus (RVFV) is an important mosquito-borne virus that can cause severe disease manifestations in humans including ocular damage, vision loss, late-onset encephalitis, and hemorrhagic fever. In ruminants, RVFV can cause high mortality rates in young animals and high rates of abortion in pregnant animals resulting in an enormous negative impact on the economy of affected regions. To date, no licensed vaccines in humans or anti-RVFV therapeutics for animal or human use are available.

A ring-like accretion structure in M87 connecting its black hole and jet.

The nearby radio galaxy M87 is a prime target for studying black hole accretion and jet formation. Event Horizon Telescope observations of M87 in 2017, at a wavelength of 1.3 mm, revealed a ring-like structure, which was interpreted as gravitationally lensed emission around a central black hole.

Mechanistic insight into the efficient packaging of antigenomic S RNA into Rift Valley fever virus particles.

Rift Valley fever virus (RVFV), a bunyavirus, has a single-stranded, negative-sense tri-segmented RNA genome, consisting of L, M and S RNAs. An infectious virion carries two envelope glycoproteins, Gn and Gc, along with ribonucleoprotein complexes composed of encapsidated viral RNA segments. The antigenomic S RNA, which serves as the template of the mRNA encoding a nonstructural protein, NSs, an interferon antagonist, is also efficiently packaged into RVFV particles.

Revisiting how People with Schizophrenia Spend Their Days: Associations of lifetime milestone Achievements with Daily Activities examined with Ecological Momentary Assessment.

Milestone achievements are reduced in people with schizophrenia and are lower in comparison to people with bipolar disorder. However, it is not clear what the implications are for engagement in momentary activities based on milestone achievements. Further, some recent research has suggested that psychotic symptoms are associated with challenges in self-assessment of activities, but there is less information about the correlations of milestone achievements and ongoing psychotic symptoms.

Cumulene carbenes in TMC-1: Astronomical discovery of -HC .

We report the first detection in space of the cumulene carbon chain -HC. A total of eleven rotational transitions, with = 7-10 and = 0 and 1, were detected in TMC-1 in the 31.0-50.

The sulphur saga in TMC-1: Discovery of HCSCN and HCSCCH.

We report the detection, for the first time in space, of cyano thioformaldehyde (HCSCN) and propynethial (HCSCCH) towards the starless core TMC-1. Cyano thioformaldehyde presents a series of prominent - and -type lines, which are the strongest previously unassigned features in our Q-band line survey of TMC-1. Remarkably, HCSCN is four times more abundant than cyano formaldehyde (HCOCN).

O-bearing complex organic molecules at the cyanopolyyne peak of TMC-1: detection of CHCHO, CHOH, HCOOCH, and CHOCH.

We report the detection of the oxygen-bearing complex organic molecules propenal (CHCHO), vinyl alcohol (CHOH), methyl formate (HCOOCH), and dimethyl ether (CHOCH) toward the cyanopolyyne peak of the starless core TMC-1. These molecules are detected through several emission lines in a deep Q-band line survey of TMC-1 carried out with the Yebes 40m telescope. These observations reveal that the cyanopolyyne peak of TMC-1, which is the prototype of cold dark cloud rich in carbon chains, contains also O-bearing complex organic molecules like HCOOCH and CHOCH, which have been previously seen in a handful of cold interstellar clouds.

Detection of deuterated methylcyanoacetylene, CHDCN, in TMC-1.

We report the first detection in space of the single deuterated isotopologue of methylcyanoacetylene, CHDCN. A total of fifteen rotational transitions, with = 8-12 and = 0 and 1, were identified for this species in TMC-1 in the 31.0-50.

Thiols in the ISM: first detection of HC(O)SH and confirmation of CHSH.

The chemical compounds carrying the thiol group (-SH) have been considered essential in recent prebiotic studies regarding the polymerization of amino acids. We have searched for this kind of compounds toward the Galactic Centre quiescent cloud G+0.693-0.

Pure hydrocarbon cycles in TMC-1: Discovery of ethynyl cyclopropenylidene, cyclopentadiene and indene.

We report the detection for the first time in space of three new pure hydrocarbon cycles in TMC-1: -CHCCH (ethynyl cyclopropenylidene), -CH (cyclopentadiene) and -CH (indene). We derive a column density of 3.1 × 10 cm for the former cycle and similar values, in the range (1-2) × 10 cm, for the two latter molecules.

Using a Meta-cognitive Wisconsin Card Sorting Test to measure introspective accuracy and biases in schizophrenia and bipolar disorder.

People with schizophrenia (SCZ) and bipolar disorder (BD) have challenges in self-evaluation of their cognitive and functional performance (introspective accuracy). They also manifest response biases, with tendencies toward overestimation. This study aimed to examine objective test performance, momentary judgments of performance, momentary confidence, and subsequent global judgments of performance on a metacognitive version of the Wisconsin Card Sorting Test (WCST).

Discovery in space of ethanolamine, the simplest phospholipid head group.

Cell membranes are a key element of life because they keep the genetic material and metabolic machinery together. All present cell membranes are made of phospholipids, yet the nature of the first membranes and the origin of phospholipids are still under debate. We report here the presence of ethanolamine in space, [Formula: see text]OH, which forms the hydrophilic head of the simplest and second-most-abundant phospholipid in membranes.

Characterization of the Molecular Interactions That Govern the Packaging of Viral RNA Segments into Rift Valley Fever Phlebovirus Particles.

Rift Valley fever phlebovirus (RVFV) has a single-stranded, negative-sense RNA genome, consisting of L, M, and S segments. The virion carries two envelope glycoproteins, Gn and Gc, along with ribonucleoprotein complexes (RNPs), composed of encapsidated genomes carrying N protein and the viral polymerase, L protein. A quantitative analysis of the profile of viral RNA segments packaged into RVFV particles showed that all three genomic RNA segments had similar packaging abilities, whereas among antigenomic RNA segments, the antigenomic S RNA, which serves as the template for the transcription of mRNA expressing the RVFV virulence factor, NSs, displayed a significantly higher packaging ability.

TMC-1, the starless core sulfur factory: Discovery of NCS, HCCS, HCCS, HCCCS, and CS and detection of CS.

We report the detection of the sulfur-bearing species NCS, HCCS, HCCS, HCCCS, and CS for the first time in space. These molecules were found towards TMC-1 through the observation of several lines for each species. We also report the detection of CS for the first time in a cold cloud through the observation of five lines in the 31-50 GHz range.

Discovery of allenyl acetylene, HCCCHCCH, in TMC-1. A study of the isomers of CH.

We present the discovery in TMC-1 of allenyl acetylene, HCCCHCCH, through the observation of nineteen lines with a signal-to-noise ratio ~4-15. For this species, we derived a rotational temperature of 7±1K and a column density of 1.2±0.

Discovery of the propargyl radical (CHCCH) in TMC-1: one of the most abundant radicals ever found and a key species for cyclization to benzene in cold dark clouds.

We present the first identification in interstellar space of the propargyl radical (CHCCH). This species was observed in the cold dark cloud TMC-1 using the Yebes 40m telescope. The six strongest hyperfine components of the 2-1 rotational transition, lying at 37.

Discovery of CHCHCCH and detection of HCCN, HCN, CHCHCN, and, tentatively, CHCHCCH in TMC-1.

We present the discovery in TMC-1 of vinyl acetylene, CHCHCCH, and the detection, for the first time in a cold dark cloud, of HCCN, HCN, and CHCHCN. A tentative detection of CHCHCCH is also reported. The column density of vinyl acetylene is (1.

Comprehensive rotational study and astronomical search for cyclopropanecarboxaldehyde.

Context: At least a dozen molecules with a formyl group (HCO) have been observed to date in the interstellar medium (ISM), suggesting that other such species exist and remain to be discovered. However, there is still a lack of high-resolution spectroscopic data for simple molecular species of this type that could provide a basis for their detection.

Aims: Cyclopropanecarboxaldehyde, c-CHCHO, is a small molecule containing a formyl group and is therefore an interesting candidate for astrophysical detection.

A study of CHN isomers in TMC-1: line by line detection of HCCCHCN.

We present Yebes 40m telescope observations of the three most stable CHN isomers towards the cyanopolyyne peak of TMC-1. We have detected 13 transitions from CHCN (A and E species), 16 lines from CHCCHCN, and 27 lines (a-type and b-type) from HCCCHCN. We thus provide a robust confirmation of the detection of HCCCHCN and CHCCHCN in space.

Discovery of the acetyl cation, CHCO, in space and in the laboratory.

Using the Yebes 40m and IRAM 30m radiotelescopes, we detected two series of harmonically related lines in space that can be fitted to a symmetric rotor. The lines have been seen towards the cold dense cores TMC-1, L483, L1527, and L1544. High level of theory calculations indicate that the best possible candidate is the acetyl cation, CHCO, which is the most stable product resulting from the protonation of ketene.

Space and laboratory discovery of HC .

We report the detection in TMC-1 of the protonated form of CS. The discovery of the cation HCS was carried through the observation of four harmonically related lines in the Q band using the Yebes 40m radiotelescope, and is supported by accurate calculations and laboratory measurements of its rotational spectrum. We derive a column density (HCS) = (2.

Cloud-cloud collision as drivers of the chemical complexity in Galactic Centre molecular clouds.

G+0.693-0.03 is a quiescent molecular cloud located within the Sagittarius B2 (Sgr B2) star-forming complex.