Balanced Biochemical Reactions: A New Approach to Unify Chemical and Biochemical Thermodynamics

A novel procedure is presented which, by balancing elements and electric charge of biochemical reactions which occur at constant pH and pMg, allows assessing the thermodynamics properties of reaction ΔrG′0, ΔrH′0, ΔrS′0 and the change in binding of hydrogen and magnesium ions of these reactions. This procedure of general applicability avoids the complex calculations required by the use of the Legendre transformed thermodynamic properties of formation ΔfG′0, ΔfH′0 and ΔfS′0 hitherto considered an obligatory prerequisite to deal with the thermodynamics of biochemical reactions. As a consequence, the term “conditional” is proposed in substitution of “Legendre transformed” to indicate these thermodynamics properties. It is also shown that the thermodynamic potential G is fully adequate to give a criterion of spontaneous chemical change for all biochemical reactions and then that the use of the Legendre transformed G′ is unnecessary. The procedure proposed can be applied to any biochemical reaction, making possible to re-unify the two worlds of chemical and biochemical thermodynamics, which so far have been treated separately

Exploiting map information for self-supervised learning in motion forecasting

Inspired by recent developments regarding the application of self-supervised learning (SSL), we devise an auxiliary task for trajectory prediction that takes advantage of map-only information such as graph connectivity with the intent of improving map comprehension and generalization. We apply this auxiliary task through two frameworks - multitasking and pretraining. In either framework we observe significant improvement of our baseline in metrics such as $\mathrm{minFDE}_6$ (as much as 20.3%) and $\mathrm{MissRate}_6$ (as much as 33.3%), as well as a richer comprehension of map features demonstrated by different training configurations. The results obtained were consistent in all three data sets used for experiments: Argoverse, Interaction and NuScenes. We also submit our new pretrained model's results to the Interaction challenge and achieve $\textit{1st}$ place with respect to $\mathrm{minFDE}_6$ and $\mathrm{minADE}_6$

Chemical and biochemical thermodynamics reunification (IUPAC Technical Report)

Abstract According to the 1994 IUBMB-IUPAC Joint Commission on Biochemical Nomenclature (JCBN) on chemical and biochemical reactions, two categories of thermodynamics, based on different concepts and different formalisms, are established: (i) chemical thermodynamics, which employ conventional thermodynamic potentials to deal with chemical reactions [1], [2], [3]; and (ii) biochemical thermodynamics, which employ transformed thermodynamic quantities to deal with biochemical reactions based on the formalism proposed by Alberty [4], [5], [6], [7]. We showed that the two worlds of chemical and biochemical thermodynamics, which so far have been treated separately, can be reunified within the same thermodynamic framework. The thermodynamics of chemical reactions, in which all species are explicitly considered with their atoms and charge balanced, are compared with the transformed thermodynamics generally used to treat biochemical reactions where atoms and charges are not balanced. The transformed thermodynamic quantities suggested by Alberty are obtained by a mathematical transformation of the usual thermodynamic quantities. The present analysis demonstrates that the transformed values for Δr G′0 and Δr H′0 can be obtained directly, without performing any transformation, by simply writing the chemical reactions with all the pseudoisomers explicitly included and the elements and charges balanced. The appropriate procedures for computing the stoichiometric coefficients for the pseudoisomers are fully explained by means of an example calculation for the biochemical ATP hydrolysis reaction. It is concluded that the analysis reunifies the "two separate worlds" of conventional thermodynamics and transformed thermodynamics

Notch signaling sustains the expression of Mcl-1 and the activity of eIF4E to promote cell survival in CLL

In chronic lymphocytic leukemia (CLL), Notch1 and Notch2 signaling is constitutively activated and contributes to apoptosis resistance. We show that genetic inhibition of either Notch1 or Notch2, through small-interfering RNA, increases apoptosis of CLL cells and is associated with decreased levels of the anti-apoptotic protein Mcl-1. Thus, Notch signaling promotes CLL cell survival at least in part by sustaining Mcl-1 expression. In CLL cells, an enhanced Notch activation also contributes to the increase in Mcl-1 expression and cell survival induced by IL-4.Mcl-1 downregulation by Notch targeting is not due to reduced transcription or degradation by caspases, but in part, to increased degradation by the proteasome. Mcl-1 downregulation by Notch targeting is also accompanied by reduced phosphorylation of eukaryotic translation initiation factor 4E (eIF4E), suggesting that this protein is another target of Notch signaling in CLL cells.Overall, we show that Notch signaling sustains CLL cell survival by promoting Mcl-1 expression and eIF4E activity, and given the oncogenic role of these factors, we underscore the therapeutic potential of Notch inhibition in CLL

Deciphering the Molecular Recognition Mechanism of Multidrug Resistance Staphylococcus aureus NorA Efflux Pump Using a Supervised Molecular Dynamics Approach

The use and misuse of antibiotics has resulted in critical conditions for drug-resistant bacteria emergency, accelerating the development of antimicrobial resistance (AMR). In this context, the co-administration of an antibiotic with a compound able to restore sufficient antibacterial activity may be a successful strategy. In particular, the identification of efflux pump inhibitors (EPIs) holds promise for new antibiotic resistance breakers (ARBs). Indeed, bacterial efflux pumps have a key role in AMR development; for instance, NorA efflux pump contributes to Staphylococcus aureus (S. aureus) resistance against fluoroquinolone antibiotics (e.g., ciprofloxacin) by promoting their active extrusion from the cells. Even though NorA efflux pump is known to be a potential target for EPIs development, the absence of structural information about this protein and the little knowledge available on its mechanism of action have strongly hampered rational drug discovery efforts in this area. In the present work, we investigated at the molecular level the substrate recognition pathway of NorA through a Supervised Molecular Dynamics (SuMD) approach, using a NorA homology model. Specific amino acids were identified as playing a key role in the efflux pump-mediated extrusion of its substrate, paving the way for a deeper understanding of both the mechanisms of action and the inhibition of such efflux pumps

Efficiency and costs of the health management in an organic dairy farm where we use unconventional medicines

The EU organic regulation explicitly promote the use of unconventional therapies, like homoeopathy and phytotherapy. The aim of the present study was to investigate the efficiency and the costs of these treatment methods. From December 2006 to September 2008, we analyzed the data recorded in an organic dairy farm where the animals are normally treated by classical unicistic homeopathy and phytotherapy, and only when indispensable, by allophaty, antiparasitic drugs, surgery and vaccines. The use of homeopathy resulted to be predominant in comparison with the others treatments. Besides, our trial showed that homeopathy and phytotherapy could be used to treat, with good outcomes, the majority of diseases that occur in a dairy cattle farm, even if, sometimes, conventional medicines have to be used. The costs for unconventional treatments are very low in comparison with conventional ones. This will allow the spreading of unconventional medicines in the Italian organic farms

Chemical analysis of prestellar cores in Ophiuchus yields short timescales and rapid collapse

Sun-like stars form from the contraction of cold and dense interstellar clouds. How the collapse proceeds and what are the main physical processes driving it, however, is still under debate and a final consensus on the timescale of the process has not been reached. Does this contraction proceed slowly, sustained by strong magnetic fields and ambipolar diffusion, or is it driven by fast collapse with gravity dominating the entire process? One way to answer this question is to measure the age of prestellar cores through statistical methods based on observations or via reliable chemical chronometers, which should better reflect the physical conditions of the cores. Here we report APEX observations of ortho-H$_2$D$^+$ and para-D$_2$H$^+$ for six cores in the Ophiuchus complex and combine them with detailed three-dimensional magneto-hydrodynamical simulations including chemistry, providing a range of ages for the observed cores up to 200 kyr. The outcome of our simulations and subsequent analysis provides a good match with the observational results in terms of physical (core masses and volume densities) and dynamical parameters such as the Mach number and the virial parameter. We show that models of fast collapse successfully reproduce the observed range of chemical abundance ratios as the timescales to reach the observed stages is comparable to the dynamical time of the cores (i.e. the free-fall time) and much shorter than the ambipolar diffusion time, measured from the electron fraction in the simulations. To confirm that this ratio can be used to distinguish between different star-formation scenarios a larger (statistically relevant) sample of star-forming cores should be explored.Comment: submitted to A&A, 12 pages, 5 figures, 4 table

Enhancement of lysosomal glycohydrolase activity in human primary B lymphocytes during spontaneous apoptosis.

It has been shown that lysosomes are involved in B cell apoptosis but lysosomal glycohydrolases have never been investigated during this event. In this study we determined the enzymatic activities of some lysosomal glycohydrolases in human tonsil B lymphocytes (TBL) undergoing in vitro spontaneous apoptosis. Fluorimetric methods were used to evaluate the activities of β-hexosaminidases, α-mannosidase, β-mannosidase, β-galactosidase, β-glucuronidase and α-fucosidase. Results show that in TBL during spontaneous apoptosis, there is a significant increase in the activity of β-hexosaminidases, α-mannosidase, β-mannosidase and β-galactosidase. Also β-glucuronidase and α-fucosidase activities increase but not in a significant manner. Further studies on β-hexosaminidases revealed that also mRNA expression of the α- and β-subunits, which constitute these enzymes, increases during spontaneous TBL apoptosis. When TBL are protected from apoptosis by the thiol molecule N-acetyl-L-cysteine (NAC), there is no longer any increase in glycohydrolase activities and mRNA expression of β-hexosaminidase α- and β-subunits. This study demonstrates for the first time that the activities and expression of some lysosomal glycohydrolases are enhanced in TBL during spontaneous apoptosis and that these increases are prevented when TBL apoptosis is inhibited