Plants measure day or night lengths to coordinate specific developmental changes with a favorable season. In rice (Oryza sativa), the reproductive phase is initiated by exposure to short days when ...expression of HEADING DATE 3a (Hd3a) and RICE FLOWERING LOCUS T 1 (RFT1) is induced in leaves. The cognate proteins are components of the florigenic signal and move systemically through the phloem to reach the shoot apical meristem (SAM). In the SAM, they form a transcriptional activation complex with the bZIP transcription factor OsFD1 to start panicle development. Here, we show that Hd3a and RFT1 can form transcriptional activation or repression complexes also in leaves and feed back to regulate their own transcription. Activation complexes depend on OsFD1 to promote flowering. However, additional bZIPs, including Hd3a BINDING REPRESSOR FACTOR1 (HBF1) and HBF2, form repressor complexes that reduce Hd3a and RFT1 expression to delay flowering. We propose that Hd3a and RFT1 are also active locally in leaves to fine-tune photoperiodic flowering responses.
Migraine is a common neurological disorder impairing the quality of life of patients. The condition requires, as an acute or prophylactic line of intervention, the frequent use of drugs acting on the ...central nervous system (CNS). The long-term impact of these medications on cognition and neurodegeneration has never been consistently assessed. The paper reviews pharmacological migraine treatments and discusses their biological and clinical effects on the CNS. The different anti-migraine drugs show distinct profiles concerning neurodegeneration and the risk of cognitive deficits. These features should be carefully evaluated when prescribing a pharmacological treatment as many migraineurs are of scholar or working age and their performances may be affected by drug misuse. Thus, a reconsideration of therapy guidelines is warranted. Furthermore, since conflicting results have emerged in the relationship between migraine and dementia, future studies must consider present and past pharmacological regimens as potential confounding factors.
•First manic episodes can occur in Sars-Cov-2 infections, even in patients with mild or absent systemic symptoms.•Sars-Cov-2-related mania started on average after twelve days from the infection ...onset.•In some cases, abnormal neuroradiology, neurophysiology, or laboratory findings were observed (a complete workup is recommended to ensure appropriate treatment).
Sars-CoV-2 is a respiratory virus that can access the central nervous system, as indicated by the presence of the virus in patients’ cerebrospinal fluid and the occurrence of several neurological syndromes during and after COVID-19. Growing evidence indicates that Sars-CoV-2 can also trigger the acute onset of mood disorders or psychotic symptoms. COVID-19-related first episodes of mania, in subjects with no known history of bipolar disorder, have never been systematically analyzed. Thus, the present study assesses a potential link between the two conditions. This systematic review analyzes cases of first appearance of manic episodes associated with COVID-19. Clinical features, pharmacological therapies, and relationships with pre-existing medical conditions are also appraised.
Medical records of twenty-three patients fulfilling the current DSM-5 criteria for manic episode were included. Manic episodes started, on average, after 12.71±6.65 days from the infection onset. Psychotic symptoms were frequently reported. 82.61% of patients exhibited delusions, whereas 39.13% of patients presented hallucinations. A large discrepancy in the diagnostic workups was observed.
Mania represents an underestimated clinical presentation of COVID-19. Further studies should focus on the pathophysiological substrates of COVID-19-related mania and pursue appropriate and specific diagnostic and therapeutic workups.
Inhibitor of Apoptosis Proteins (IAPs) is highly conserved negative regulators of apoptosis overexpressed in many cancer cells. Based on their endogenous antagonist, Smac/DIABLO, mimic compounds ...(Smac‐mimetics, SMs) have been developed to inhibit IAPs prosurvival activity, showing promising effects in advanced phases of clinical trials. Since different IAP homologs play distinctive roles in cancer cell survival and immunomodulation, SM‐induced apoptosis proceeds through diverse mechanisms. After binding to their BIR3 domain, SMs have been shown to rapidly induce auto‐ubiquitylation and degradation of cellular IAPs (cIAPs), thus leading to cell death mainly by activation of the noncanonical NF‐κB pathway. For this reason, we started the BIR3‐driven design of compounds selective for cIAP1 and with reduced affinity for X‐linked IAP (XIAP), in order to focus SMs antitumor activity on cIAPs degradation. In this work, we describe the crystal structures of the BIR3 domains of cIAP1 and XIAP, each in complex with a cIAP1‐selective SM (SM130 and SM114, respectively). The two SMs displayed 23‐ and 32‐fold higher affinity for cIAP1‐BIR3 over XIAP‐BIR3 in molecular displacement experiments based on fluorescence polarization. In vitro cell‐based assays confirmed that both selective SMs triggered apoptosis in cancer cells with different efficiencies by inducing caspases‐3, ‐8, and ‐9‐independent cIAP1 degradation. The design of cIAPs‐selective compounds represents an innovative approach in the field of anticancer drugs development, being useful to elucidate different prosurvival mechanisms and to reduce the adverse effects of pan‐IAPs compounds in cancer therapy.
Database
Structural data are available in the Protein Data Bank database under the accession codes 6EXW (cIAP1‐BIR3/SM130 complex) and 6EY2 (XIAP‐BIR3/SM114 complex).
Pan‐IAPs antagonists are antitumor drugs targeting the BIR3 domain of all IAPs. The structural study pointed out features useful to design cIAP1‐selective antagonists, which demonstrate their predominant action on cIAP1 both in cell‐free and in cell‐based assays. The work aims to elucidate the different IAPs‐dependent mechanisms of cell survival and overcome the adverse effects of IAPs antagonists in cancer therapy.
Background
The 2019 Coronavirus (SARS-CoV-2) is a novel respiratory virus which causes Coronavirus Disease19 (COVID-19). Although the predominant clinical picture of COVID-19 is represented by ...respiratory symptoms, neurological manifestations are being increasingly recognized. Headache, in particular migraine-like and tension types, has been largely reported in patients suffering from COVID-19 both in the acute and the healing phase of the infection. New daily persistent headache (NDPH) is a primary headache characterized by persistent and daily painful symptoms, with pain becoming continuous and non-remitting within 24 h, and lasting more than 3 months. Even though an increasing number of reports describe patients who develop a persistent headache, diagnosis of NPDH has been rarely explored in the context of COVID-19.
Methods
Two patients with persistent headache and Sars-CoV-2 infection were identified. Both underwent a full clinical and neuroradiological evaluation. Blood sample with inflammatory biomarkers search was also performed.
Results
According to International Classifications of Headache Disorders diagnosis of probable new daily persistent headache was made. The treatment with high doses of steroids was associated with relief of symptoms.
Conclusions
Our report described two cases of probable NDPH due to SARS-CoV-2 infection. Clinical evaluation of COVID-19 patients presenting with persistent headache should take into consideration NDPH. Given the supposed major role for neuroinflammation in the genesis of Sars-CoV-2-driven NDPH, immunomodulatory therapy should be promptly started. In line with this hypothesis, we obtained a good therapeutic response to short-term high dose of corticosteroids.
In Duchenne muscular dystrophy (DMD), telomere shortening has been postulated to contribute to the failure of regenerative activity promoting the premature senescence of satellite cells. The aim of ...the present study was to investigate the telomere length and the expression of telomeric repeat-binding factor-1 (TRF1), poly (ADP-ribose) polymerase-1 (PARP1) and mouse telomerase reverse transcriptase (MTERT) in gastrocnemius, tibialis anterior and diaphragm muscles of the murine model of DMD, the
mdx
mouse and whether a chronic protocol of forced exercise impacts on them. Our results confirmed a telomere shortening in
mdx
muscles, more evident in the diaphragm, in which exercise induced a greater shortening than in wild-type mice. Moreover, we showed for the first time in
mdx
an increased TRF1 and PARP1 expression and an augmented activity of MTERT, further enhanced by exercise. These results reinforce the hypothesis that a deregulation of mechanisms involved in telomere length occurs and may pave the way for the test of compounds targeting proteins modulating telomere maintenance as a novel strategy to treat dystrophinopathies.
Facio-scapulo-humeral dystrophy (FSHD) is a common muscular dystrophy featuring progressive weakness, mostly involving facial muscles and the scapular cingulum. FSHD is an autosomal-dominant ...inherited disease driven by the contraction of the D4Z4 region of chromosome 4. Patients with FSHD have a high life expectancy, about 20% of FSHD subjects need wheelchairs in their 50s, and extramuscular involvement is rare, however, no epidemiological studies have been carried out on this data.Our case describes a man affected by FSHD who, in his 60s, developed atypical Parkinsonism diagnosed as progressive supranuclear palsy (PSP).FSHD symptoms can hide other neuromuscular diseases developed on ageing. This case highlights the importance of considering possible overlaps with other neurodegenerative diseases.
β‐proteins are constantly threatened by the risk of aggregation because β‐sheets are inherently structured for edge‐to‐edge interactions. To avoid native‐like aggregation, evolution has resulted in a ...set of strategies that prevent intermolecular β‐interactions. Acylphosphatase from Sulfolobus solfataricus (Sso AcP) represents a suitable model for the study of such a process. Under conditions promoting aggregation, Sso AcP acquires a native‐like conformational state whereby an unstructured N‐terminal segment interacts with the edge β‐strand B4 of an adjacent Sso AcP molecule. Because B4 is poorly protected against aggregation, this interaction triggers the aggregation cascade without the need for unfolding. Recently, three single Sso AcP mutants (V84D, Y86E and V84P) were designed to engineer additional protection against aggregation in B4 and were observed to successfully impair native‐like aggregation in all three variants at the expense of a lower stability. To understand the structural basis of the reduced aggregation propensity and lower stability, the crystal structures of the Sso AcP variants were determined in the present study. Structural analysis reveals that the V84D and Y86E mutations exert protection by the insertion of an edge negative charge. A conformationally less regular B4 underlies protection against aggregation in the V84P mutant. The thermodynamic basis of instability is discussed. Moreover, kinetic experiments indicate that aggregation of the three mutants is not native‐like and is independent of the interaction between B4 and the unstructured N‐terminal segment. The reported data rationalize previous evidence regarding Sso AcP native‐like aggregation and provide a basis for the design of aggregation‐free proteins. DATABASE: The atomic coordinates and related experimental data for the Sso AcP mutants V84P, V84D, ΔN11 Y86E have been deposited in the Protein Data Bank under accession numbers 4OJ3, 4OJG and 4OJH, respectively. STRUCTURED DIGITAL ABSTRACT: • Sso AcP and Sso AcP bind by fluorescence technology (View interaction).
The RNA-dependent protein kinase PKR plays a central role in the antiviral defense of vertebrates by shutting down protein translation upon detection of viral dsRNA in the cytoplasm. In some teleost ...fish, PKZ, a homolog of PKR, performs the same function, but surprisingly, instead of dsRNA binding domains, it harbors two Z-DNA/Z-RNA-binding domains belonging to the Zalpha domain family. Zalpha domains have also been found in other proteins, which have key roles in the regulation of interferon responses such as ADAR1 and DNA-dependent activator of IFN-regulatory factors (DAI) and in viral proteins involved in immune response evasion such as the poxviral E3L and the Cyprinid Herpesvirus 3 ORF112. The underlying mechanism of nucleic acids binding and stabilization by Zalpha domains is still unclear. Here, we present two crystal structures of the zebrafish PKZ Zalpha domain (DrZalpha(PKZ)) in alternatively organized complexes with a (CG)6 DNA oligonucleotide at 2 and 1.8 Å resolution. These structures reveal novel aspects of the Zalpha interaction with DNA, and they give insights on the arrangement of multiple Zalpha domains on DNA helices longer than the minimal binding site.
Spontaneous aggregation of folded and soluble native proteins in vivo is still a poorly understood process. A prototypic example is the D76N mutant of beta-2 microglobulin (β2m) that displays an ...aggressive aggregation propensity. Here we investigate the dynamics of β2m by X-ray crystallography, solid-state NMR, and molecular dynamics simulations to unveil the effects of the D76N mutation. Taken together, our data highlight the presence of minor disordered substates in crystalline β2m. The destabilization of the outer strands of D76N β2m accounts for the increased aggregation propensity. Furthermore, the computational modeling reveals a network of interactions with residue D76 as a keystone: this model allows predicting the stability of several point mutants. Overall, our study shows how the study of intrinsic dynamics in crystallo can provide crucial answers on protein stability and aggregation propensity. The comprehensive approach here presented may well be suited for the study of other folded amyloidogenic proteins.
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