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Primary familial brain calcification (PFBC) is characterized by calcium deposition in the brain, causing progressive movement disorders, psychiatric symptoms, and cognitive decline. PFBC is a heterogeneous disorder currently linked to variants in six different genes, but most patients remain genetically undiagnosed. Here, we identify biallelic NAA60 variants in ten individuals from seven families with autosomal recessive PFBC. The NAA60 variants lead to loss-of-function with lack of protein N-terminal (Nt)-acetylation activity. We show that the phosphate importer SLC20A2 is a substrate of NAA60 in vitro. In cells, loss of NAA60 caused reduced surface levels of SLC20A2 and a reduction in extracellular phosphate uptake. This study establishes NAA60 as a causal gene for PFBC, provides a possible biochemical explanation of its disease-causing mechanisms and underscores NAA60-mediated Nt-acetylation of transmembrane proteins as a fundamental process for healthy neurobiological functioning.

Abstract Perturbation theory in asymptotically free quantum field theories is asymptotic. The factorially growing perturbative coefficients carry information about non-perturbative corrections, which can be related to renormalons and instantons. Using the Wiener-Hopf technique we determine the full analytic solution for the free energy density in the two dimensional O(N) sigma models. For N > 3 there are no instantons, and we found that the perturbative series carries all the information about the non-perturbative corrections. However, in the O(3) case, we identify several non-perturbative sectors that are not related to the asymptotics of the perturbative series. The number of sectors depends on the observables: for the ground-state energy density we identify three sectors, which we attribute to instantons. For the free energy density in the running perturbative coupling we found infinitely many sectors.

Abstract Surface display of functional groups with specific reactivity around living cells is an emerging, low cost and highly eco-compatible technology that serves multiple applications, ranging from basic biochemical studies to biomedicine, therapeutics and environmental sciences. Conversely to classical methods exploiting hazardous organic synthesis of precursors or monovalent functionalization via genetics, here we perform functional decoration of individual living microalgae using suitable biocoatings based on polydopamine, a melanin-like synthetic polymer. Here we demonstrate the one-pot synthesis of a functional polydopamine bearing phenylboronic units which can decorate the living cell surfaces via a direct ester formation between boronic units and surface glycoproteins. Furthermore, biosorption of fluorescent sugars on functionalized cell membranes is triggered, demonstrating that these organic coatings act as biocompatible soft shells, still functional and reactive after cell engineering.

Background: Cesarean scar pregnancy (CSP) has become more frequent as a direct consequence of the increased number of cesarean deliveries and the advances in imaging. Although some cases are characterized by spontaneous resolution, unrecognized or mishandled CSP has the potential to cause both fetal and maternal morbidity and mortality. However, due to its infrequency, there is no agreement on the best management. Objective: The purpose of this study was to evaluate the safety, the risks and effectiveness of medical therapy with methotrexate and mifepristone to better understand its role in CSP therapy. Design: This study is a systematic review. Data Sources and Methods: The electronic databases PubMed, Medline, and Scopus were comprehensively searched until December 2023. Medical Subject Headings terms (Cesarean scar pregnancy) AND (Methotrexate) AND (Mifepristone) AND (Medical Therapy) were used to identify the relevant records. Due to the rarity of this pathology, the studies included are all case reports or case series. The methodological quality of the included studies was assessed using the JBI Critical Appraisal Checklist for case reports. Results: We included in our review a total of seven cases reported in five manuscripts at the end of the screening process. Our review suggests that this type of combination treatment can be considered. The success rate is 71.4%. Treatment seems to be most effective when beta human chorionic gonadotropin (B-hCG) is below 5,000 mUi/ml and when the gestational sac is less than 20 mm. The absence of fetal heartbeat seems to be a positive prognostic factor for a positive outcome. Conclusion: Methotrexate and mifepristone administration can be considered as an alternative first-line effective treatment, especially in case of pregnancy with B-hCG

Abstract Introduction In addition to produce biogas, the anaerobic digestion process releases a significant quantity of solid digestate (DG), a C‐rich byproduct suitable both as a soil improver and as a biosorbent of organic and inorganic pollutants. This study considered a mixed biowaste DG and two aerobic DG‐derivatives such as compost (CP) and vermicompost (VC). Materials and Methods A multianalytical approach was adopted to comprehensively characterize DG, CP and VC. Elemental composition was determined by total reflection X‐ray fluorescence (TXRF) spectroscopy; micromorphological features, surface elements and surface area were evaluated by scanning electron microscopy coupled with energy dispersive X‐ray (SEM‐EDX) technique and Brunauer–Emmett–Teller (BET) analysis; functional properties were investigated by attenuated total reflectance‐Fourier transform infrared (FTIR‐ATR) spectroscopy and Raman spectroscopy. Results TXRF analysis showed that DG had the highest K content (~8.9 g kg−1), while VC had the maximum P, S and Ca contents, and appreciable levels of essential plant micronutrients, such as Mn, Fe, Cu and Zn. SEM‐EDX technique evidenced heterogeneous surfaces and low porosity of all materials. BET analysis showed relevant specific surface areas of DG, CP and, especially, VC (~1.6 m2 g−1). FTIR‐ATR and Raman spectroscopy allowed to identify various aliphatic and aromatic functional groups of the materials and provided information on their major molecular classes, such as lignocellulosic moieties and inorganic components. The latter techniques also contributed to understand the chemical transformations of the DG after the aerobic treatments. Conclusion The overall results obtained confirmed the valuable potential of these materials in improving the physical and chemical fertility of the soil and in retaining pollutants, with consequent benefits for mantaining soil productivity and preserving ecosystem health.

Abstract Magma ascending through Earth’s crust undergoes complex chemical and physical changes that may induce crystallization, a process that contributes to lead the magmatic system toward a thermodynamic state of equilibrium. The diverse cooling and deformative regimes suffered by magmas heavily influence crystallization rates, solidification timescales, and consequently, the rheological evolution of magma. This, in turn, significantly impacts the dynamics of volcanic plumbing systems and the associated eruptive styles. Here, we investigate the rheological changes in Stromboli magma (Italy) during disequilibrium crystallization under non-isothermal subliquidus conditions. By systematically varying the cooling rate (1-10 °C/min) and the shear rate (1-10 s−1), we find that cooling rates significantly influence the solidification path of the basalt, whereas shear rates have a subordinate effect. By comparing our results with literature data on basalts from Mt. Etna (Italy), characterized by higher TiO2 and FeOtot contents, we observed distinct timescales and rates of solidification, contributing to unique eruptive dynamics in these volcanic plumbing systems.

Abstract Two-dimensional (2D) materials combine many fascinating properties that make them more interesting than their three-dimensional counterparts for a variety of applications. For example, 2D materials exhibit stronger electron-phonon and electron-hole interactions, and their energy gaps and effective carrier masses can be easily tuned. Surprisingly, published band gaps of several 2D materials obtained with the G W approach, the state-of-the-art in electronic-structure calculations, are quite scattered. The details of these calculations, such as the underlying geometry, the starting point, the inclusion of spin-orbit coupling, and the treatment of the Coulomb potential can critically determine how accurate the results are. Taking monolayer MoS2 as a representative material, we employ the linearized augmented planewave + local orbital method to systematically investigate how all these aspects affect the quality of G 0 W 0 calculations, and also provide a summary of literature data. We conclude that the best overall agreement with experiments and coupled-cluster calculations is found for G 0 W 0 results with HSE06 as a starting point including spin-orbit coupling, a truncated Coulomb potential, and an analytical treatment of the singularity at q = 0.

Abstract Craniofacial malformations, often associated with syndromes, are prevalent birth defects. Emerging evidence underscores the importance of m6A modifications in various bioprocesses such as stem cell differentiation, tissue development, and tumorigenesis. Here, in vivo, experiments with zebrafish models revealed that mettl3-knockdown embryos at 144 h postfertilization exhibited aberrant craniofacial features, including altered mouth opening, jaw dimensions, ethmoid plate, tooth formation and hypoactive behavior. Similarly, low METTL3 expression inhibited the proliferation and migration of BMSCs, HEPM cells, and DPSCs. Loss of METTL3 led to reduced mRNA m6A methylation and PSEN1 expression, impacting craniofacial phenotypes. Co-injection of mettl3 or psen1 mRNA rescued the level of Sox10 fusion protein, promoted voluntary movement, and mitigated abnormal craniofacial phenotypes induced by mettl3 knockdown in zebrafish. Mechanistically, YTHDF1 enhanced the mRNA stability of m6A-modified PSEN1, while decreased METTL3-mediated m6A methylation hindered β-catenin binding to PSEN1, suppressing Wnt/β-catenin signaling. Pharmacological activation of the Wnt/β-catenin pathway partially alleviated the phenotypes of mettl3 morphant and reversed the decreases in cell proliferation and migration induced by METTL3 silencing. This study elucidates the pivotal role of METTL3 in craniofacial development via the METTL3/YTHDF1/PSEN1/β-catenin signaling axis.

Abstract Primary familial brain calcification (PFBC) is characterized by calcium deposition in the brain, causing progressive movement disorders, psychiatric symptoms, and cognitive decline. PFBC is a heterogeneous disorder currently linked to variants in six different genes, but most patients remain genetically undiagnosed. Here, we identify biallelic NAA60 variants in ten individuals from seven families with autosomal recessive PFBC. The NAA60 variants lead to loss-of-function with lack of protein N-terminal (Nt)-acetylation activity. We show that the phosphate importer SLC20A2 is a substrate of NAA60 in vitro. In cells, loss of NAA60 caused reduced surface levels of SLC20A2 and a reduction in extracellular phosphate uptake. This study establishes NAA60 as a causal gene for PFBC, provides a possible biochemical explanation of its disease-causing mechanisms and underscores NAA60-mediated Nt-acetylation of transmembrane proteins as a fundamental process for healthy neurobiological functioning.

Abstract Background/Objectives Rare genetic disorders causing specific congenital developmental abnormalities often manifest in single families. Investigation of disease-causing molecular features are most times lacking, although these investigations may open novel therapeutic options for patients. In this study, we aimed to identify the genetic cause in an Iranian patient with severe skeletal dysplasia and to model its molecular function in zebrafish embryos. Results The proband displays short stature and multiple skeletal abnormalities, including mesomelic dysplasia of the arms with complete humero-radio-ulna synostosis, arched clavicles, pelvic dysplasia, short and thin fibulae, proportionally short vertebrae, hyperlordosis and mild kyphosis. Exome sequencing of the patient revealed a novel homozygous c.374G > T, p.(Arg125Leu) missense variant in MSGN1 (NM_001105569). MSGN1, a basic-Helix–Loop–Helix transcription factor, plays a crucial role in formation of presomitic mesoderm progenitor cells/mesodermal stem cells during early developmental processes in vertebrates. Initial in vitro experiments show protein stability and correct intracellular localization of the novel variant in the nucleus and imply retained transcription factor function. To test the pathogenicity of the detected variant, we overexpressed wild-type and mutant msgn1 mRNA in zebrafish embryos and analyzed tbxta (T/brachyury/ntl). Overexpression of wild-type or mutant msgn1 mRNA significantly reduces tbxta expression in the tailbud compared to control embryos. Mutant msgn1 mRNA injected embryos depict a more severe effect, implying a gain-of-function mechanism. In vivo analysis on embryonic development was performed by clonal msgn1 overexpression in zebrafish embryos further demonstrated altered cell compartments in the presomitic mesoderm, notochord and pectoral fin buds. Detection of ectopic tbx6 and bmp2 expression in these embryos hint to affected downstream signals due to Msgn1 gain-of-function. Conclusion In contrast to loss-of-function effects described in animal knockdown models, gain-of-function of MSGN1 explains the only mildly affected axial skeleton of the proband and rather normal vertebrae. In this context we observed notochord bending and potentially disruption of pectoral fin buds/upper extremity after overexpression of msgn1 in zebrafish embryos. The latter might result from Msgn1 function on mesenchymal stem cells or on chondrogenesis in these regions. In addition, we detected ectopic tbx6 and bmp2a expression after gain of Msgn1 function in zebrafish, which are interconnected to short stature, congenital scoliosis, limb shortening and prominent skeletal malformations in patients. Our findings highlight a rare, so far undescribed skeletal dysplasia syndrome associated with a gain-of-function mutation in MSGN1 and hint to its molecular downstream effectors.

Approximately half a billion people—5% of the world’s population—suffer from disabling hearing impairment (HI) according to the WHO ( http://www.who.int/features/factfiles/deafness/en/ ). HI commonly hampers speech acquisition, leads to social isolation and increases risk for depression and cognitive decline. One to two per thousand children are born with disabling HI and over 50% of sensorineural HI is caused by defects in individual genes (deafness genes) of which roughly 150 have been identified so far ( http://hereditaryhearingloss.org/ ). In case of profound hearing impairment or deafness, cochlear implants that bypass the dysfunctional or lost sensory hair cells and electrically stimulate the auditory nerve partially restore hearing. However, hearing with cochlear implants has shortcomings such as limited understanding of speech in background noise. So, there remains a major unmet medical need for improved hearing restoration (Wolf et al, 2022). Yet, despite major research efforts, a causal treatment based on pharmacology, gene therapy, or stem cells had, so far, not been clinically available. Now, this is finally changing at least for some patients: first in human trials prove the concept for inner ear gene therapy of otoferlin-related synaptic deafness.

Abstract We develop a new method to calculate finite size corrections for form factors in two-dimensional integrable quantum field theories. We extract these corrections from the excited state expectation value of bilocal operators in the limit when the operators are far apart. We elaborate the finite size effects explicitly up to the 3rd Lüscher order and conjecture the structure of the general form. We also fully recover the explicitly known massive fermion finite volume form factors.

Although herbicides are essential for global agriculture and controlling weeds, they impact soil microbial communities and CO2 emissions. However, the effects of herbicides, tillage systems, and nitrogen fertilisation on CO2 emissions under different environmental conditions are poorly understood. This review explores how various agricultural practices and inputs affect CO2 emissions and addresses the impact of pest-management strategies, tillage systems, and nitrogen fertiliser usage on CO2 emissions using multiple databases. Key findings indicate that both increased and decreased tendencies in greenhouse gas (GHG) emissions were observed, depending on the herbicide type, dose, soil properties, and application methods. Several studies reported a positive correlation between CO2 emissions and increased agricultural production. Combining herbicides with other methods effectively controls emissions with minimal chemical inputs. Conservation practices like no-tillage were more effective than conventional tillage in mitigating carbon emissions. Integrated pest management, conservation tillage, and nitrogen fertiliser rate optimisation were shown to reduce herbicide use and soil greenhouse gas emissions. Fertilisers are similarly important; depending on the dosage, they may support yield or harm the soil. Fertiliser benefits are contingent on appropriate management practices for specific soil and field conditions. This review highlights the significance of adaptable management strategies that consider local environmental conditions and can guide future studies and inform policies to promote sustainable agriculture practices worldwide.

The pathophysiology of diverticular disease (DD) is not well outlined. Recent studies performed on the DD human ex vivo model have shown the presence of a predominant transmural oxidative imbalance whose origin remains unknown. Considering the central role of mitochondria in oxidative stress, the present study evaluates their involvement in the alterations of DD clinical phenotypes. Colonic surgical samples of patients with asymptomatic diverticulosis, complicated DD, and controls were analyzed. Electron microscopy, protein expression, and cytofluorimetric analyses were performed to assess the contribution of mitochondrial oxidative stress. Functional muscle activity was tested on cells in response to contractile and relaxant agents. To assess the possibility of reverting oxidative damages, N-acetylcysteine was tested on an in vitro model. Compared with the controls, DD tissues showed a marketed increase in mitochondrial number and fusion accompanied by the altered mitochondrial electron transport chain complexes. In SMCs, the mitochondrial mass increase was accompanied by altered mitochondrial metabolic activity supported by a membrane potential decrease. Ulteriorly, a decrease in antioxidant content and altered contraction–relaxation dynamics reverted by N-acetylcysteine were observed. Therefore, the oxidative stress-driven alterations resulted in mitochondrial impairment. The beneficial effects of antioxidant treatments open new possibilities for tailored therapeutic strategies that have not been tested for this disease.

We revisit the problem of integrability breaking in free fermionic quantum spin chains. We investigate the so-called adiabatic gauge potential (AGP), which was recently proposed as an accurate probe of quantum chaos. We also study the so-called weak integrability breaking, which occurs if the dynamical effects of the perturbation do not appear at leading order in the perturbing parameter. A recent statement in the literature claimed that integrability breaking should generally lead to an exponential growth of the AGP norm with respect to the volume. However, afterwards it was found that weak integrability breaking is a counter-example, leading to a cross-over between polynomial and exponential growth. Here we show that in free fermionic systems the AGP norm always grows polynomially, if the perturbation is local with respect to the fermions, even if the perturbation strongly breaks integrability. As a by-product of our computations we also find, that in free fermionic spin chains there are operators which weakly break integrability, but which are not associated with known long range deformations.