Towards the Definition of the Molecular Hallmarks of Idiopathic Membranous Nephropathy in Serum Proteome: A DIA-PASEF Approach

Idiopathic membranous nephropathy (IMN) is a pathologically defined disorder of the glomerulus, primarily responsible for nephrotic syndromes (NS) in nondiabetic adults. The underlying molecular mechanisms are still not completely clarified. To explore possible molecular and functional signatures, an optimised mass spectrometry (MS) method based on next-generation data-independent acquisition combined with ion-mobility was applied to serum of patients affected by IMN (n = 15) or by other glomerulopathies (PN) (n = 15). The statistical comparison highlighted a panel of 57 de-regulated proteins with a significant increase in lipoprotein-related proteins (APOC1, APOB, APOA1, APOL1 and LCAT) and a substantial quantitative alteration of key serpins (including A4, D1, A7, A6, F2, F1 and 1) possibly associated with IMN or NS and podocyte stress. A critical dysregulation in metabolisms of lipids (e.g., VLDL assembly and clearance) likely to be related to known hyperlipidemia in IMN, along with involvement of non-classical complement pathways and a putative enrolment of ficolin-2 in sustaining the activation of the lectin-mediated complement system have been pinpointed. Moreover, mannose receptor CD206 (MRC1-down in IMN) and biotinidase (BTD-up in IMN) are able alone to accurately distinguish IMN vs. PN. To conclude, our work provides key proteomic insights into the IMN complexity, opening the way to an efficient stratification of MN patients

Plasma Proteomic Variables Related to COVID-19 Severity: An Untargeted nLC-MS/MS Investigation

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection leads to a wide range of clinical manifestations and determines the need for personalized and precision medicine. To better understand the biological determinants of this heterogeneity, we explored the plasma proteome of 43 COVID-19 patients with different outcomes by an untargeted liquid chromatography-mass spectrometry approach. The comparison between asymptomatic or pauci-symptomatic subjects (MILDs), and hospitalised patients in need of oxygen support therapy (SEVEREs) highlighted 29 proteins emerged as differentially expressed: 12 overexpressed in MILDs and 17 in SEVEREs. Moreover, a supervised analysis based on a decision-tree recognised three proteins (Fetuin-A, Ig lambda-2chain-C-region, Vitronectin) that are able to robustly discriminate between the two classes independently from the infection stage. In silico functional annotation of the 29 deregulated proteins pinpointed several functions possibly related to the severity; no pathway was associated exclusively to MILDs, while several only to SEVEREs, and some associated to both MILDs and SEVEREs; SARS-CoV-2 signalling pathway was significantly enriched by proteins up-expressed in SEVEREs (SAA1/2, CRP, HP, LRG1) and in MILDs (GSN, HRG). In conclusion, our analysis could provide key information for 'proteomically' defining possible upstream mechanisms and mediators triggering or limiting the domino effect of the immune-related response and characterizing severe exacerbations

In Silico Reconstitution of Actin-Based Symmetry Breaking and Motility

Computational modeling and experimentation in a model system for actin-based force generation explain how actin networks initiate and maintain directional movement

Intercalation of small molecules into DNA in chromatin is primarily controlled by superhelical constraint

The restricted access of regulatory factors to their binding sites on DNA wrapped around the nucleosomes is generally interpreted in terms of molecular shielding exerted by nucleosomal structure and internucleosomal interactions. Binding of proteins to DNA often includes intercalation of hydrophobic amino acids into the DNA. To assess the role of constrained superhelicity in limiting these interactions, we studied the binding of small molecule intercalators to chromatin in close to native conditions by laser scanning cytometry. We demonstrate that the nucleosome-constrained superhelical configuration of DNA is the main barrier to intercalation. As a result, intercalating compounds are virtually excluded from the nucleosome-occupied regions of the chromatin. Binding of intercalators to extranucleosomal regions is limited to a smaller degree, in line with the existence of net supercoiling in the regions comprising linker and nucleosome free DNA. Its relaxation by inducing as few as a single nick per ~50 kb increases intercalation in the entire chromatin loop, demonstrating the possibility for long-distance effects of regulatory potential

Nuclear organization and 3D chromatin architecture in cognition and neuropsychiatric disorders

The current view of neuroplasticity depicts the changes in the strength and number of synaptic connections as the main physical substrate for behavioral adaptation to new experiences in a changing environment. Although transcriptional regulation is known to play a role in these synaptic changes, the specific contribution of activity-induced changes to both the structure of the nucleus and the organization of the genome remains insufficiently characterized. Increasing evidence indicates that plasticity-related genes may work in coordination and share architectural and transcriptional machinery within discrete genomic foci. Here we review the molecular and cellular mechanisms through which neuronal nuclei structurally adapt to stimuli and discuss how the perturbation of these mechanisms can trigger behavioral malfunction

Determinants of Indonesian Coal Commodity Export Before and Post the Spread of the Covid-19 Policy

As a fossil fuel, most of Indonesia's coal production to date is exported to various countries that still rely on this commodity as a source of electrical energy. With this pandemic, Indonesia's coal exports have decreased. Therefore, the need for coal to meet domestic demand will affect coal exports so that it will have an impact on economic growth. To determine the effect, this study was tested using qualitative research methods. The test results show that during the pandemic, coal consumption or demand decreases and has a negative impact on domestic economic growth

Laser driven nuclear physics at ELI–NP

High power lasers have proven being capable to produce high energy γ-rays, charged particles and neutrons, and to induce all kinds of nuclear reactions. At ELI, the studies with high power lasers will enter for the first time into new domains of power and intensities: 10 PW and 1023 W/cm2. While the development of laser based radiation sources is the main focus at the ELI-Beamlines pillar of ELI, at ELI-NP the studies that will benefit from High Power Laser System pulses will focus on Laser Driven Nuclear Physics (this TDR, acronym LDNP, associated to the E1 experimental area), High Field Physics and QED (associated to the E6 area) and fundamental research opened by the unique combination of the two 10 PW laser pulses with a gamma beam provided by the Gamma Beam System (associated to E7 area). The scientific case of the LDNP TDR encompasses studies of laser induced nuclear reactions, aiming for a better understanding of nuclear properties, of nuclear reaction rates in laser-plasmas, as well as on the development of radiation source characterization methods based on nuclear techniques. As an example of proposed studies: the promise of achieving solid-state density bunches of (very) heavy ions accelerated to about 10 MeV/nucleon through the RPA mechanism will be exploited to produce highly astrophysical relevant neutron rich nuclei around the N~126 waiting point, using the sequential fission-fusion scheme, complementary to any other existing or planned method of producing radioactive nuclei. The studies will be implemented predominantly in the E1 area of ELI-NP. However, many of them can be, in a first stage, performed in the E5 and/or E4 areas, where higher repetition laser pulses are available, while the harsh X-ray and electromagnetic pulse (EMP) environments are less damaging compared to E1. A number of options are discussed through the document, having an important impact on the budget and needed resources. Depending on the TDR review and subsequent project decisions, they may be taken into account for space reservation, while their detailed design and implementation will be postponed. The present TDR is the result of contributions from several institutions engaged in nuclear physics and high power laser research. A significant part of the proposed equipment can be designed, and afterwards can be built, only in close collaboration with (or subcontracting to) some of these institutions. A Memorandum of Understanding (MOU) is currently under preparation with each of these key partners as well as with others that are interested to participate in the design or in the future experimental program