Ongoing declines for the world's amphibians in the face of emerging threats.

Systematic assessments of species extinction risk at regular intervals are necessary for informing conservation action1,2. Ongoing developments in taxonomy, threatening processes and research further underscore the need for reassessment3,4. Here we report the findings of the second Global Amphibian Assessment, evaluating 8,011 species for the International Union for Conservation of Nature Red List of Threatened Species. We find that amphibians are the most threatened vertebrate class (40.7% of species are globally threatened). The updated Red List Index shows that the status of amphibians is deteriorating globally, particularly for salamanders and in the Neotropics. Disease and habitat loss drove 91% of status deteriorations between 1980 and 2004. Ongoing and projected climate change effects are now of increasing concern, driving 39% of status deteriorations since 2004, followed by habitat loss (37%). Although signs of species recoveries incentivize immediate conservation action, scaled-up investment is urgently needed to reverse the current trends.

Meeting report - Cell dynamics: host-pathogen interface.

Two years into the most significant infectious disease event of our generation, infections have populated every conversation and in-depth understanding of host-pathogen interactions has, perhaps, never been more important. In a successful return to in-person conferences, the host-pathogen interface was the focus of the third Cell Dynamics meeting, which took place at the glorious Wotton House in Surrey, UK. The meeting organised by Michaela Gack, Maximiliano Gutierrez, Dominique Soldati-Favre and Michael Way gathered an international group of scientists who shared their recent discoveries and views on numerous aspects, including cell-autonomous defence mechanisms, pathogen interactions with host cytoskeletal or membrane dynamics, and cellular immune regulation. More than 30 years into the beginning of cellular microbiology as a field, the meeting exhibited the unique aspect of the host-pathogen interface in uncovering the fundamentals of both pathogens and their hosts.

Intracellular delivery of Parkin-RING0-based fragments corrects Parkin-induced mitochondrial dysfunction through interaction with SLP-2.

BACKGROUND: Loss-of-function mutations in the PRKN gene, encoding Parkin, are the most common cause of autosomal recessive Parkinson's disease (PD). We have previously identified mitoch ondrial Stomatin-like protein 2 (SLP-2), which functions in the assembly of respiratory chain proteins, as a Parkin-binding protein. Selective knockdown of either Parkin or SLP-2 led to reduced mitochondrial and neuronal function in neuronal cells and Drosophila, where a double knockdown led to a further worsening of Parkin-deficiency phenotypes. Here, we investigated the minimal Parkin region involved in the Parkin-SLP-2 interaction and explored the ability of Parkin-fragments and peptides from this minimal region to restore mitochondrial function. METHODS: In fibroblasts, human induced pluripotent stem cell (hiPSC)-derived neurons, and neuroblastoma cells the interaction between Parkin and SLP-2 was investigated, and the Parkin domain responsible for the binding to SLP-2 was mapped. High resolution respirometry, immunofluorescence analysis and live imaging were used to analyze mitochondrial function. RESULTS: Using a proximity ligation assay, we quantitatively assessed the Parkin-SLP-2 interaction in skin fibroblasts and hiPSC-derived neurons. When PD-associated PRKN mutations were present, we detected a significantly reduced interaction between the two proteins. We found a preferential binding of SLP-2 to the N-terminal part of Parkin, with a highest affinity for the RING0 domain. Computational modeling based on the crystal structure of Parkin protein predicted several potential binding sites for SLP-2 within the Parkin RING0 domain. Amongst these, three binding sites were observed to overlap with natural PD-causing missense mutations, which we demonstrated interfere substantially with the binding of Parkin to SLP-2. Finally, delivery of the isolated Parkin RING0 domain and a Parkin mini-peptide, conjugated to cell-permeant and mitochondrial transporters, rescued compromised mitochondrial function in Parkin-deficient neuroblastoma cells and hiPSC-derived neurons with endogenous, disease causing PRKN mutations. CONCLUSIONS: These findings place further emphasis on the importance of the protein-protein interaction between Parkin and SLP-2 for the maintenance of optimal mitochondrial function. The possibility of restoring an abolished binding to SLP-2 by delivering the Parkin RING0 domain or the Parkin mini-peptide involved in this specific protein-protein interaction into cells might represent a novel organelle-specific therapeutic approach for correcting mitochondrial dysfunction in Parkin-linked PD.

Functional recovery of secondary tropical forests.

One-third of all Neotropical forests are secondary forests that regrow naturally after agricultural use through secondary succession. We need to understand better how and why succession varies across environmental gradients and broad geographic scales. Here, we analyze functional recovery using community data on seven plant characteristics (traits) of 1,016 forest plots from 30 chronosequence sites across the Neotropics. By analyzing communities in terms of their traits, we enhance understanding of the mechanisms of succession, assess ecosystem recovery, and use these insights to propose successful forest restoration strategies. Wet and dry forests diverged markedly for several traits that increase growth rate in wet forests but come at the expense of reduced drought tolerance, delay, or avoidance, which is important in seasonally dry forests. Dry and wet forests showed different successional pathways for several traits. In dry forests, species turnover is driven by drought tolerance traits that are important early in succession and in wet forests by shade tolerance traits that are important later in succession. In both forests, deciduous and compound-leaved trees decreased with forest age, probably because microclimatic conditions became less hot and dry. Our results suggest that climatic water availability drives functional recovery by influencing the start and trajectory of succession, resulting in a convergence of community trait values with forest age when vegetation cover builds up. Within plots, the range in functional trait values increased with age. Based on the observed successional trait changes, we indicate the consequences for carbon and nutrient cycling and propose an ecologically sound strategy to improve forest restoration success.

Leaf anatomy of seven endemic species of Glicophyllum (Malpighiaceae) in Brazil.

Glicophyllum is well supported, presenting four homoplasies, easily differentiated from the other genera of the clade due to characteristics related to the reproductive organs, which can make the identification of their species difficult when they are not in the reproductive phase. Therefore, there are provided the leaf anatomical and morphological description of the leaf glands of seven species of Glicophyllum to assist in the identification of their species. The samples for the study were obtained from several national and international herbaria, sectioned freehand, stained with basic fuchsin - astra blue and compared through a binary matrix using the Sorensen's coefficient in the MVSP software. Among the leaf anatomical characters found, the following stand out: presence/absence of trichomes; petiole contour; contour of the main vein; organization of the mesophyll, presence/absence of bundle sheath extension and the surface of the glands. In this study, an identification key with leaf anatomical data is presented for the first time, demonstrating the applicability of leaf anatomy for the taxonomy of Glicophyllum. In the multivariate analysis, it is observed that the characteristics of leaf venation and topology of the glands are more representative to differentiate the taxa. Therefore, the data obtained can support future taxonomic and phylogenetic studies of the genus.

Characterizing molecular and synaptic signatures in mouse models of late-onset Alzheimer's disease independent of amyloid and tau pathology.

INTRODUCTION: MODEL-AD (Model Organism Development and Evaluation for Late-Onset Alzheimer's Disease) is creating and distributing novel mouse models with humanized, clinically relevant genetic risk factors to capture the trajectory and progression of late-onset Alzheimer's disease (LOAD) more accurately. METHODS: We created the LOAD2 model by combining apolipoprotein E4 (APOE4), Trem2*R47H, and humanized amyloid-beta (Aß). Mice were subjected to a control diet or a high-fat/high-sugar diet (LOAD2+HFD). We assessed disease-relevant outcome measures in plasma and brain including neuroinflammation, Aß, neurodegeneration, neuroimaging, and multi-omics. RESULTS: By 18 months, LOAD2+HFD mice exhibited sex-specific neuron loss, elevated insoluble brain Aß42, increased plasma neurofilament light chain (NfL), and altered gene/protein expression related to lipid metabolism and synaptic function. Imaging showed reductions in brain volume and neurovascular uncoupling. Deficits in acquiring touchscreen-based cognitive tasks were observed. DISCUSSION: The comprehensive characterization of LOAD2+HFD mice reveals that this model is important for preclinical studies seeking to understand disease trajectory and progression of LOAD prior to or independent of amyloid plaques and tau tangles. HIGHLIGHTS: By 18 months, unlike control mice (e.g., LOAD2 mice fed a control diet, CD), LOAD2+HFD mice presented subtle but significant loss of neurons in the cortex, elevated levels of insoluble Ab42 in the brain, and increased plasma neurofilament light chain (NfL). Transcriptomics and proteomics showed changes in gene/proteins relating to a variety of disease-relevant processes including lipid metabolism and synaptic function. In vivo imaging revealed an age-dependent reduction in brain region volume (MRI) and neurovascular uncoupling (PET/CT). LOAD2+HFD mice also demonstrated deficits in acquisition of touchscreen-based cognitive tasks.

Sodium and lithium exert differential effects on the central carbon metabolism of Debaryomyces hansenii through the glyoxylate shunt regulation.

Debaryomyces hansenii is a halotolerant/halophilic yeast usually found in salty environments. The yeast accumulated sodium at high concentrations, which improved growth in salty media. In contrast, lithium was toxic even at low concentrations and its presence prevented cell proliferation. To analyse the responses to both cations, metabolite levels, enzymatic activities and gene expression were determined, showing that NaCl and LiCl trigger different cellular responses. At high concentrations of NaCl (0.5 or 1.5 M) cells accumulated higher amounts of the intermediate metabolites glyoxylate and malate and, at the same time, the levels of intracellular oxoglutarate decreased. Additionally, 0.5 M NaCl increased the activity of the enzymes isocitrate lyase and malate synthase involved in the synthesis of glyoxylate and malate respectively and decreased the activity of isocitrate dehydrogenase. Moreover, transcription of the genes coding for isocitrate lyase and malate synthase was activated by NaCl. Also, cells accumulated phosphate upon NaCl exposure. None of these effects was provoked when LiCl (0.1 or 0.3 M) was used instead of NaCl. Lithium induced accumulation of higher amounts of oxoglutarate and decreased the concentrations of glyoxylate and malate to non-detectable levels. Cells incubated with lithium also showed higher activity of the isocitrate dehydrogenase and neither increased isocitrate lyase and malate synthase activities nor the transcription of the corresponding genes. In summary, we show that sodium, but not lithium, up regulates the shunt of the glyoxylic acid in D. hansenii and we propose that this is an important metabolic adaptation to thrive in salty environments.

Equated hospitalization rate of patients with inflammatory rheumatic diseases as compared to normal population in 2°wave SARSCoV2 infection.

OBJECTIVE: To investigate the clinical manifestations and outcome of COVID-19 in patients with inflammatory rheumatic and musculoskeletal disease (iRMD) as compared with the general population. METHODS: This is a case-control study of patients selected from the South-Tyrol public health service-Italy with and without iRMD affected by COVID-19. We included patients ≥18 years and with a positive SARS-CoV-2 PCR test between 1.10.2020 and 01.03.2021. Cases were identified by linking the diagnosis of a rheumatic disease with PCR test positivity; these were matched in a 1:1.8 (planned 1:2) ratio for age, sex, and date of COVID-19 diagnosis with people from the general population. The outcomes of primary interest were hospitalization and severe course (intensive care unit, mechanical ventilation/extracorporeal membrane oxygenation, death). RESULTS: The study population consisted of 561 COVID-19 patients, of which 201 (mean age 60.4 years; 65.2% female) were patients with iRMD and 360 were controls from the general population (59.8 years; 64.7% female). The majority of iRMD patients (88.6%) received an immunosuppressive drug at time of COVID-19 diagnosis, 36.3% were under glucocorticoids. COVID-19 related hospitalization (12.4% vs 10.6%, p= 0.49), severe course (5.0% vs 5.3%, p= 1.00), and mortality (3.5% vs 4.4%, p= 0.66) were similar between groups. Among hospitalized patients, mechanic ventilation was more common in iRMD patients than in controls [n = 5 (20.0%) vs n = 1 (2.6%), p= 0.035]. CONCLUSIONS: Our study indicates similar rates for admission, severe course and mortality between patients with iRMD and controls affected by COVID-19. Among hospitalized patients, mechanical ventilation was more frequently required in the iRMD group.

Palmitoylated acyl protein thioesterase APT2 deforms membranes to extract substrate acyl chains.

Many biochemical reactions require controlled recruitment of proteins to membranes. This is largely regulated by posttranslational modifications. A frequent one is S-acylation, which consists of the addition of acyl chains and can be reversed by poorly understood acyl protein thioesterases (APTs). Using a panel of computational and experimental approaches, we dissect the mode of action of the major cellular thioesterase APT2 (LYPLA2). We show that soluble APT2 is vulnerable to proteasomal degradation, from which membrane binding protects it. Interaction with membranes requires three consecutive steps: electrostatic attraction, insertion of a hydrophobic loop and S-acylation by the palmitoyltransferases ZDHHC3 or ZDHHC7. Once bound, APT2 is predicted to deform the lipid bilayer to extract the acyl chain bound to its substrate and capture it in a hydrophobic pocket to allow hydrolysis. This molecular understanding of APT2 paves the way to understand the dynamics of APT2-mediated deacylation of substrates throughout the endomembrane system.

Behavioral effects induced by the cannabidiol analogs HU-502 and HU-556.

Cannabidiol is a phytocannabinoid that lacks the psychotomimetic properties of Δ9-tetrahydrocannabinol (THC), the main psychoactive Cannabis sativa component. Cannabidiol has several potential therapeutic properties, including anxiolytic, antidepressant, and antipsychotic; however, cannabidiol has low oral bioavailability, which can limit its clinical use. Here, we investigated if two cannabidiol analogs, HU-502 and HU-556, would be more potent than cannabidiol in behavioral tests predictive of anxiolytic, antidepressant, and antipsychotic effects. Different doses (0.01-3 mg/kg; intraperitoneally) of HU-556 and HU-502 were tested in male Swiss mice submitted to the elevated plus maze (EPM), forced swimming test (FST), and amphetamine-induced-prepulse inhibition (PPI) disruption and hyperlocomotion. Cannabidiol is effective in these tests at a dose range of 15-60 mg/kg in mice. We also investigated if higher doses of HU-556 (3 and 10 mg/kg) and HU-502 (10 mg/kg) produced the cannabinoid tetrad (hypolocomotion, catalepsy, hypothermia, and analgesia), which is induced by THC-like compounds. HU-556 (0.1 and 1 mg/kg) increased the percentage of open arm entries (but not time) in the EPM, decreased immobility time in the FST, and attenuated amphetamine-induced PPI disruption. HU-502 (1 and 3 mg/kg) decreased amphetamine-induced hyperlocomotion and PPI impairment. HU-556, at high doses, caused catalepsy and hypolocomotion, while HU-502 did not. These findings suggest that similar to cannabidiol, HU-556 could induce anxiolytic, antidepressant, and antipsychotic-like effects and that HU-502 has antipsychotic properties. These effects were found at a dose range devoid of cannabinoid tetrad effects.

Modelling of surface reactions and diffusion mediated by bulk diffusion.

We develop a continuum framework applicable to solid-state hydrogen storage, cell biology and other scenarios where the diffusion of a single constituent within a bulk region is coupled via adsorption/desorption to reactions and diffusion on the boundary of the region. We formulate content balances for all relevant constituents and develop thermodynamically consistent constitutive equations. The latter encompass two classes of kinetics for adsorption/desorption and chemical reactions-fast and Marcelin-De Donder, and the second class includes mass action kinetics as a special case. We apply the framework to derive a system consisting of the standard diffusion equation in bulk and FitzHugh-Nagumo type surface reaction-diffusion system of equations on the boundary. We also study the linear stability of a homogeneous steady state in a spherical region and establish sufficient conditions for the occurrence of instabilities driven by surface diffusion. These findings are verified through numerical simulations which reveal that instabilities driven by diffusion lead to the emergence of steady-state spatial patterns from random initial conditions and that bulk diffusion can suppress spatial patterns, in which case temporal oscillations can ensue. We include an extension of our framework that accounts for mechanochemical coupling when the bulk region is occupied by a deformable solid. This article is part of the theme issue 'Foundational issues, analysis and geometry in continuum mechanics'.

"NO" Time in Fear Response: Possible Implication of Nitric-Oxide-Related Mechanisms in PTSD.

Post-traumatic stress disorder (PTSD) is a psychiatric condition characterized by persistent fear responses and altered neurotransmitter functioning due to traumatic experiences. Stress predominantly affects glutamate, a neurotransmitter crucial for synaptic plasticity and memory formation. Activation of the N-Methyl-D-Aspartate glutamate receptors (NMDAR) can trigger the formation of a complex comprising postsynaptic density protein-95 (PSD95), the neuronal nitric oxide synthase (nNOS), and its adaptor protein (NOS1AP). This complex is pivotal in activating nNOS and nitric oxide (NO) production, which, in turn, activates downstream pathways that modulate neuronal signaling, including synaptic plasticity/transmission, inflammation, and cell death. The involvement of nNOS and NOS1AP in the susceptibility of PTSD and its comorbidities has been widely shown. Therefore, understanding the interplay between stress, fear, and NO is essential for comprehending the maintenance and progression of PTSD, since NO is involved in fear acquisition and extinction processes. Moreover, NO induces post-translational modifications (PTMs), including S-nitrosylation and nitration, which alter protein function and structure for intracellular signaling. Although evidence suggests that NO influences synaptic plasticity and memory processing, the specific role of PTMs in the pathophysiology of PTSD remains unclear. This review highlights pathways modulated by NO that could be relevant to stress and PTSD.

Long-term oncological and surgical outcomes after Video Endoscopic Inguinal Lymphadenectomy (VEIL) in patients with penile cancer.

OBJECTIVE: To report outcomes from the largest multicenter series of penile cancer patients undergoing video endoscopic inguinal lymphadenectomy (VEIL). MATERIALS AND METHODS: Retrospective multicenter analysis. Authors of 21 centers from the Penile Cancer Collaborative Coalition-Latin America (PeC-LA) were included. All centers performed the procedure following the same previously described standardized technique. Inclusion criteria included penile cancer patients with no palpable lymph nodes and intermediate/high-risk disease and those with non-fixed palpable lymph nodes less than 4 cm in diameter. Categorical variables are shown as percentages and frequencies whereas continuous variables as mean and range. RESULTS: From 2006 to 2020, 210 VEIL procedures were performed in 105 patients. Mean age was 58 (45-68) years old. Mean operative time was 90 minutes (60-120). Mean lymph node yield was 10 nodes (6-16). Complication rate was 15.7%, including severe complications in 1.9% of procedures. Lymphatic and skin complications were noted in 8.6 and 4.8% of patients, respectively. Histopathological analysis revealed lymph node involvement in 26.7% of patients with non-palpable nodes. Inguinal recurrence was observed in 2.8% of patients. 10y- overall survival was 74.2% and 10-y cancer specific survival was 84.8%. CSS for pN0, pN1, pN2 and pN3 were 100%, 82.4%, 72.7% and 9.1%, respectively. CONCLUSION: VEIL seems to offer appropriate long term oncological control with minimal morbidity. In the absence of non-invasive stratification measures such as dynamic sentinel node biopsy, VEIL emerged as the alternative for the management of non-bulky lymph nodes in penile cancer.

Synchronous colorectal cancer and abdominal aortic aneurysm treated simultaneously. Is a one-stage surgery a feasible treatment?

The finding of synchronous abdominal aortic aneurysm and colorectal cancer is rare. There is no consensus on which is the best surgical approach, so its management remains uncertain. A 64-year-old man was diagnosed with synchronous abdominal aortic aneurysm and rectal cancer. One-stage treatment was performed: He underwent endovascular aortic repair followed by simultaneous laparoscopic tumor resection. In our experience, one-stage minimally invasive surgery could be a safe and feasible treatment for concomitant abdominal aortic aneurysm and colorectal cancer.

Irreversible Geometrothermodynamics of Open Systems in Modified Gravity.

In this work, we explore the formalism of the irreversible thermodynamics of open systems and the possibility of gravitationally generated particle production in modified gravity. More specifically, we consider the scalar-tensor representation of f(R,T) gravity, in which the matter energy-momentum tensor is not conserved due to a nonminimal curvature-matter coupling. In the context of the irreversible thermodynamics of open systems, this non-conservation of the energy-momentum tensor can be interpreted as an irreversible flow of energy from the gravitational sector to the matter sector, which, in general, could result in particle creation. We obtain and discuss the expressions for the particle creation rate, the creation pressure, and the entropy and temperature evolutions. Applied together with the modified field equations of scalar-tensor f(R,T) gravity, the thermodynamics of open systems lead to a generalization of the ΛCDM cosmological paradigm, in which the particle creation rate and pressure are considered effectively as components of the cosmological fluid energy-momentum tensor. Thus, generally, modified theories of gravity in which these two quantities do not vanish provide a macroscopic phenomenological description of particle production in the cosmological fluid filling the Universe and also lead to the possibility of cosmological models that start from empty conditions and gradually build up matter and entropy.

Spatial variations in family planning demand to limit childbearing and the demand satisfied with modern methods in sub-Saharan Africa.

BACKGROUND: There is an increasing demand for family planning to limit childbearing in sub-Saharan Africa (SSA). However, limited studies have quantified the spatial variations. This study examined: (i) the spatial patterns in the demand for family planning to limit childbearing and satisfied with modern methods, and (ii) the correlates of the demand for family planning to limit childbearing satisfied with modern methods in SSA. METHODS: This study analyzed secondary data on 306,080 married/in-union women obtained from Demographic Health Surveys conducted between 2010 and 2019 in 33 sub-Saharan African countries. We conducted exploratory spatial data analysis, with countries as the unit of analysis. We also performed regression analysis to determine the factors associated with demand for family planning to limit childbearing satisfied with modern methods in SSA. RESULTS: The mean percentage of women who demanded for family planning to limit childbearing by country was 20.5% while the mean prevalence of demand for family planning to limit childbearing satisfied with modern methods by country was 46.5%. There was a significant positive global spatial autocorrelation in the demand for family planning to limit childbearing (global Moran's I = 0.3, p = 0.001). The cluster map showed the concentration of cold spots (low-low clusters) in western and central Africa (WCA), while hot spots (high-high clusters) were concentrated in eastern and southern Africa (ESA). Also, the demand for family planning to limit childbearing satisfied with modern methods showed significant positive global spatial autocorrelation (global Moran's I = 0.2, p = 0.004) and concentration of cold spots in WCA. In the final multivariable regression model the joint family planning decision making (ß = 0.34, p < 0.001), and antenatal care (ß = 13.98, p < 0.001) were the significant factors associated with the demand for family planning to limit childbearing satisfied by modern methods. CONCLUSIONS: There are significant spatial variations in the demand for family planning to limit childbearing and the demand satisfied by modern methods, with cold spots concentrated in WCA. Promoting joint decision making by partners and increasing uptake of antenatal care may improve the demand for family planning to limit childbearing satisfied with modern methods.

In sub-Saharan Africa (SSA), studies have shown that the proportion of married women who want to stop having children has been increasing as well as the proportion using modern contraceptive methods among them. These studies also indicated that this proportion of women are higher in certain regions of Africa than the others. To extend these previous findings, we performed geographical analysis to assess how the proportion of married/in-union women who want to stop having children and the ones using modern methods among them differ geographically. Our findings indicated that neighboring countries where the proportion of married/in-union women who want to stop having children was higher than the overall average were concentrated in eastern and southern Africa (ESA), while neighboring countries in which the proportion of married/in-union women who want to stop having children was lower than the overall average were concentrated in western and central Africa (WCA). Similarly, the results also showed that neighboring countries where the proportion of married/in-union women using modern contraceptive methods among those who want to stop having children was lower than the overall average were concentrated in WCA. Our findings suggest that increasing joint decision making on family planning and uptake of antenatal care in SSA may improve the use of modern contraceptive methods among married/in-union women who want to stop childbearing.

Candida albicans Potassium Transporters.

Potassium is basic for life. All living organisms require high amounts of intracellular potassium, which fulfils multiple functions. To reach efficient potassium homeostasis, eukaryotic cells have developed a complex and tightly regulated system of transporters present both in the plasma membrane and in the membranes of internal organelles that allow correct intracellular potassium content and distribution. We review the information available on the pathogenic yeast Candida albicans. While some of the plasma membrane potassium transporters are relatively well known and experimental data about their nature, function or regulation have been published, in the case of most of the transporters present in intracellular membranes, their existence and even function have just been deduced because of their homology with those present in other yeasts, such as Saccharomyces cerevisiae. Finally, we analyse the possible links between pathogenicity and potassium homeostasis. We comment on the possibility of using some of these transporters as tentative targets in the search for new antifungal drugs.

Childhood Hypophosphatasia Associated with a Novel Biallelic ALPL Variant at the TNSALP Dimer Interface.

The goal of this study was to perform a clinical and molecular investigation in an eight-year-old female child diagnosed with hypophosphatasia (HPP). The proband and her family were evaluated by medical and dental histories, biochemical analyses, radiographic imaging, and genetic analysis of the tissue-nonspecific alkaline phosphatase (ALPL) gene. A bioinformatic analysis was performed to predict the structural and functional impact of the point mutations in the tissue-nonspecific alkaline phosphatase (TNSALP) molecule and to define their potential contribution to the phenotype. We identified a novel combination of heterozygous ALPL missense variants in the proband, p.Ala33Val and p.Asn47His, compatible with an autosomal recessive mode of inheritance and resulting in skeletal and dental phenotypes. Computational modeling showed that the affected Asn47 residue is located in the coil structure close to the N-terminal α-helix, whereas the affected Ala33 residue is localized in the N-terminal α-helix. Both affected residues are located close to the homodimer interface, suggesting they may impair TNSALP dimer formation and stability. Clinical and biochemical follow-up revealed improvements after six years of ERT. Reporting this novel combination of ALPL variants in childhood HPP provides new insights into genotype-phenotype associations for HPP and specific sites within the TNSALP molecule potentially related to a childhood-onset HPP and skeletal and dental manifestations. Beneficial effects of ERT are implicated in skeletal and dental tissues.

Zero-Biased Photoelectrochemical Detection of Cardiac Biomarker Myoglobin Based on CdSeS/ZnS Quantum Dots and Barium Titanate Perovskite.

Cardiovascular diseases are considered one of the leading causes of premature mortality of patients worldwide. Therefore, rapid diagnosis of these diseases is crucial to ensure the patient's survival. During a heart attack or severe muscle damage, myoglobin is rapidly released in the body to constitute itself as a precise biomarker of acute myocardial infarction. Thus, we described the photoelectrochemical immunosensor development to detect myoglobin. It was based on fluorine-doped tin oxide modified with CdSeS/ZnSe quantum dots and barium titanate (BTO), designated as CdSeS/ZnSQDS/BTO. It was characterized by scanning electron microscopy (SEM), energy-dispersive spectroscopy (EDX), transmission electron microscopy (TEM), X-ray diffraction (XRD), electrochemical impedance spectroscopy (EIS), and amperometry. The anodic photocurrent at the potential of 0 V (vs. Ag/AgCl) and pH 7.4 was found linearly related to the myoglobin (Mb) concentration from 0.01 to 1000 ng mL-1. Furthermore, the immunosensor showed an average recovery rate of 95.7-110.7% for the determination of myoglobin.