Data-efficient fine-tuning of foundational models for first-principles quality sublimation enthalpies.

Calculating sublimation enthalpies of molecular crystal polymorphs is relevant to a wide range of technological applications. However, predicting these quantities at first-principles accuracy - even with the aid of machine learning potentials - is a challenge that requires sub-kJ mol-1 accuracy in the potential energy surface and finite-temperature sampling. We present an accurate and data-efficient protocol for training machine learning interatomic potentials by fine-tuning the foundational MACE-MP-0 model and showcase its capabilities on sublimation enthalpies and physical properties of ice polymorphs. Our approach requires only a few tens of training structures to achieve sub-kJ mol-1 accuracy in the sublimation enthalpies and sub-1% error in densities at finite temperature and pressure. Exploiting this data efficiency, we perform preliminary NPT simulations of hexagonal ice at the random phase approximation level and demonstrate a good agreement with experiments. Our results show promise for finite-temperature modelling of molecular crystals with the accuracy of correlated electronic structure theory methods.

Crosstalk between adenine nucleotide transporter and mitochondrial swelling: experimental and computational approaches.

Mitochondrial metabolism and function are modulated by changes in matrix Ca2+. Small increases in the matrix Ca2+ stimulate mitochondrial bioenergetics, whereas excessive Ca2+ leads to cell death by causing massive matrix swelling and impairing the structural and functional integrity of mitochondria. Sustained opening of the non-selective mitochondrial permeability transition pores (PTP) is the main mechanism responsible for mitochondrial Ca2+ overload that leads to mitochondrial dysfunction and cell death. Recent studies suggest the existence of two or more types of PTP, and adenine nucleotide translocator (ANT) and FOF1-ATP synthase were proposed to form the PTP independent of each other. Here, we elucidated the role of ANT in PTP opening by applying both experimental and computational approaches. We first developed and corroborated a detailed model of the ANT transport mechanism including the matrix (ANTM), cytosolic (ANTC), and pore (ANTP) states of the transporter. Then, the ANT model was incorporated into a simple, yet effective, empirical model of mitochondrial bioenergetics to ascertain the point when Ca2+ overload initiates PTP opening via an ANT switch-like mechanism activated by matrix Ca2+ and is inhibited by extra-mitochondrial ADP. We found that encoding a heterogeneous Ca2+ response of at least three types of PTPs, weakly, moderately, and strongly sensitive to Ca2+, enabled the model to simulate Ca2+ release dynamics observed after large boluses were administered to a population of energized cardiac mitochondria. Thus, this study demonstrates the potential role of ANT in PTP gating and proposes a novel mechanism governing the cryptic nature of the PTP phenomenon.

Mobile genes in the human microbiome are structured from global to individual scales.

Recent work has underscored the importance of the microbiome in human health, and has largely attributed differences in phenotype to differences in the species present among individuals. However, mobile genes can confer profoundly different phenotypes on different strains of the same species. Little is known about the function and distribution of mobile genes in the human microbiome, and in particular whether the gene pool is globally homogenous or constrained by human population structure. Here, we investigate this question by comparing the mobile genes found in the microbiomes of 81 metropolitan North Americans with those of 172 agrarian Fiji islanders using a combination of single-cell genomics and metagenomics. We find large differences in mobile gene content between the Fijian and North American microbiomes, with functional variation that mirrors known dietary differences such as the excess of plant-based starch degradation genes found in Fijian individuals. Notably, we also observed differences between the mobile gene pools of neighbouring Fijian villages, even though microbiome composition across villages is similar. Finally, we observe high rates of recombination leading to individual-specific mobile elements, suggesting that the abundance of some genes may reflect environmental selection rather than dispersal limitation. Together, these data support the hypothesis that human activities and behaviours provide selective pressures that shape mobile gene pools, and that acquisition of mobile genes is important for colonizing specific human populations.

A Nationwide Retrospective Analysis of Out-of-Hospital Pediatric Cardiopulmonary Resuscitation Treated by Helicopter Emergency Medical Service in the Netherlands.

OBJECTIVE: There is generally limited but conflicting literature on the incidence, causes, and outcomes of pediatric out-of-hospital cardiac arrest. This study was performed to determine the incidence and outcome of pediatric out-of-hospital cardiac arrest reported by all helicopter emergency medical services in the Netherlands and to provide a description of causes and treatments and, in particular, a description of the specific interventions that can be performed by a physician-staffed helicopter emergency medical service. METHODS: A retrospective analysis was performed of all documented pediatric (0 < 18 years of age) out-of-hospital cardiac arrests from July 2015 to July 2017, attended by all 4 Dutch helicopter emergency medical service teams. RESULTS: Two hundred two out-of-hospital cardiac arrests were identified. The overall incidence in the Netherlands is 3.5 out-of-hospital cardiac arrests in children per 100,000 pediatric inhabitants. The overall survival rate for out-of-hospital cardiac arrest was 11.4%. Eleven (52%) of the survivors were in the drowning group and between 12 and 96 months of age. CONCLUSION: Helicopter emergency medical services are frequently called to pediatric out-of-hospital cardiac arrests in the Netherlands. The survival rate is normal to high compared with other countries. The 12- to 96-month age group and drowning seem to have a relatively favorable outcome.

Association Between L-OPA1 Cleavage and Cardiac Dysfunction During Ischemia-Reperfusion Injury in Rats.

BACKGROUND/AIMS: Structural and functional alterations in mitochondria, particularly, the inner mitochondrial membrane (IMM) plays a critical role in mitochondria-mediated cell death in response to cardiac ischemia-reperfusion (IR) injury. The integrity of IMM can be affected by two potential intra-mitochondrial factors: i) mitochondrial matrix swelling, and ii) proteolytic cleavage of the long optic atrophy type 1 (L-OPA1), an IMM-localized dynamin-like GTPase engaged in the regulation of structural organization and integrity of the mitochondrial cristae. However, the relationship between these two factors in response to oxidative stress remains unclear. Here, we elucidated the effects of cardiac IR injury on L-OPA1 cleavage and OMA1 activity. METHODS: Langendorff-mode perfused isolated rat hearts were subjected to 25-min of global ischemia followed by 90-min reperfusion in the presence or absence of XJB-5-131 (XJB, a mitochondria-targeting ROS scavenger) and sanglifehrin A (SfA, a permeability transition pore inhibitor). RESULTS: XJB in combination with SfA increased post-ischemic recovery of cardiac function and reduced mitochondrial ROS production at 30- and 60-min reperfusion and affected mitochondrial swelling. L-OPA1 levels were reduced in IR hearts; however, neither XJB, SfA, and their combination prevented IR-induced reduction of L-OPA1 cleavage. Likewise, IR increased the OMA1 enzymatic activity, which remained unchanged in the presence of XJB and/or SfA. CONCLUSION: IR-induced cardiac and mitochondrial dysfunctions are associated with OMA1 activation and L-OPA1 cleavage. However, XJB, SfA, and their combination do not prevent these changes despite improved heart and mitochondria function, thus, suggesting that different mechanisms can be implicated in L-OPA1 processing in response to cardiac IR injury.

Cardiac Function is not Susceptible to Moderate Disassembly of Mitochondrial Respiratory Supercomplexes.

: Mitochondrial respiratory chain supercomplexes (RCS), particularly, the respirasome, which contains complexes I, III, and IV, have been suggested to participate in facilitating electron transport, reducing the production of reactive oxygen species (ROS), and maintaining the structural integrity of individual electron transport chain (ETC) complexes. Disassembly of the RCS has been observed in Barth syndrome, neurodegenerative and cardiovascular diseases, diabetes mellitus, and aging. However, the physiological role of RCS in high energy-demanding tissues such as the heart remains unknown. This study elucidates the relationship between RCS assembly and cardiac function. Adult male Sprague Dawley rats underwent Langendorff retrograde perfusion in the presence and absence of ethanol, isopropanol, or rotenone (an ETC complex I inhibitor). We found that ethanol had no effects on cardiac function, whereas rotenone reduced heart contractility, which was not recovered when rotenone was excluded from the perfusion medium. Blue native polyacrylamide gel electrophoresis revealed significant reductions of respirasome levels in ethanol- or rotenone-treated groups compared to the control group. In addition, rotenone significantly increased while ethanol had no effect on mitochondrial ROS production. In isolated intact mitochondria in vitro, ethanol did not affect respirasome assembly; however, acetaldehyde, a byproduct of ethanol metabolism, induced dissociation of respirasome. Isopropanol, a secondary alcohol which was used as an alternative compound, had effects similar to ethanol on heart function, respirasome levels, and ROS production. In conclusion, ethanol and isopropanol reduced respirasome levels without any noticeable effect on cardiac parameters, and cardiac function is not susceptible to moderate reductions of RCS.

Prehospital Management of Peripartum Neonatal Complications by Helicopter Emergency Medical Service in the South West of the Netherlands: An Observational Study.

OBJECTIVE: Emergency medical service (EMS) is responsible for prehospital care encompassing all ages, irrespective of injury cause or medical condition, which includes peripartum emergencies. When patients require care more advanced than the level provided by the national EMS protocol, an EMS physician-staffed Dutch helicopter emergency medical service (HEMS) may be dispatched. In the Netherlands in 2016, there were 21.434 planned home births guided by midwives alone without further obstetric assistance, accounting for 12.7% of all births that year. However, there are no clear data available thus far regarding neonates requiring emergency care with or without HEMS assistance. This article reviews neonates during our study period who received medical care after birth by HEMS. METHODS: A retrospective chart review was performed including neonates born on the day of the dispatch between January 2012 and December 2017 who received additional medical care from the Rotterdam HEMS. RESULTS: Fifty-two neonates received medical care by HEMS. The majority (73.1%) were full-term (Gestational age > 37 weeks). Home delivery was intended in 63.5%, 20% of whom experienced an uncomplicated delivery but had a poor start of life. The majority of unplanned deliveries (n = 17) were preterm (70.6%). Two were born by resuscitative hysterotomy; 1 survived in good neurologic condition, and the other died at the scene. Fifteen neonates (28.9%) required cardiopulmonary resuscitation; in 2 cases, no resuscitation was started on medical grounds, and 12 of the other 13 resuscitated neonates regained return of spontaneous circulation. In 33 (63.5%) of the neonates, respiratory interventions were required; 8 (15.4%) were intubated before transport. Death was confirmed in 5 (9.6%) neonates, all preterm. CONCLUSION: During the study period, 52 neonates required medical assistance by HEMS. The 5 infants who died were all preterm. In this cohort, adequate basic life support was implemented immediately after birth either by the attending midwife, EMS, or HEMS on arrival. This suggests that prehospital first responders know the basic skills of neonatal life support.

Succinate is an inflammatory signal that induces IL-1ß through HIF-1α.

Macrophages activated by the Gram-negative bacterial product lipopolysaccharide switch their core metabolism from oxidative phosphorylation to glycolysis. Here we show that inhibition of glycolysis with 2-deoxyglucose suppresses lipopolysaccharide-induced interleukin-1ß but not tumour-necrosis factor-α in mouse macrophages. A comprehensive metabolic map of lipopolysaccharide-activated macrophages shows upregulation of glycolytic and downregulation of mitochondrial genes, which correlates directly with the expression profiles of altered metabolites. Lipopolysaccharide strongly increases the levels of the tricarboxylic-acid cycle intermediate succinate. Glutamine-dependent anerplerosis is the principal source of succinate, although the 'GABA (γ-aminobutyric acid) shunt' pathway also has a role. Lipopolysaccharide-induced succinate stabilizes hypoxia-inducible factor-1α, an effect that is inhibited by 2-deoxyglucose, with interleukin-1ß as an important target. Lipopolysaccharide also increases succinylation of several proteins. We therefore identify succinate as a metabolite in innate immune signalling, which enhances interleukin-1ß production during inflammation.

A Physician-Based Helicopter Emergency Medical Services Was Associated With an Additional 2.5 Lives Saved per 100 Dispatches of Severely Injured Pediatric Patients.

OBJECTIVE: Physician-based helicopter emergency medical services (HEMS) provide specialist medical care to the accident scene in order to improve the survival of severely injured patients. Studies that focus on the role of physician-based HEMS in pediatric trauma are scarce. The aim of this retrospective, observational study was to determine the effect of physician-based HEMS assistance on the survival of severely injured pediatric patients. METHODS: All consecutive severely injured pediatric patients (age < 18 years and Injury Severity Score > 15) treated between October 1, 2000, and February 28, 2013, were included. The survival of patients who received medical care of physician-based HEMS was compared with the survival of patients treated by an ambulance paramedic crew (ie, emergency medical services group) only. A regression model was developed for calculating the survival benefit in the physician-based HEMS group. RESULTS: A total of 308 patients were included; 112 (36%) were primarily treated by emergency medical services, and 196 (64%) patients received additional physician-based HEMS assistance on scene. The model with the best diagnostic properties and fit contained physician-based HEMS assistance, 3 components of the Glasgow Coma Scale (eye, motor, and verbal) scored prehospitally (before intubation), ordinal values for the Injury Severity Scale, systolic blood pressure, and respiratory rate. This model predicted that 5 additional patients survived because of physician-based HEMS assistance. This corresponds with 2.5 additional lives saved per 100 physician-based HEMS dispatches for severely injured pediatric patients. CONCLUSION: The data suggest that an additional 2.5 lives might be saved per 100 physician-based HEMS dispatches for severely injured pediatric patients.

Prehospital Blood Transfusions in Pediatric Patients by a Helicopter Emergency Medical Service.

OBJECTIVE: In the prehospital setting, the Nijmegen and Rotterdam helicopter emergency medical services administer packed red blood cells to critically ill or injured pediatric patients. Blood is given on scene or during transport and is derived from nearby hospitals. We summarize our experience with prehospital blood use in pediatric patients. METHODS: The databases from both the Nijmegen and Rotterdam helicopter emergency medical services were reviewed for all pediatric (< 18 years) patients who received packed red blood cells on scene or during transport to the hospital. RESULTS: Between 2007 and 2015, 10 pediatric patients out of approximately 2,400 pediatric patients received blood in the prehospital setting. The median Injury Severity Score was 41. Seven hospitals delivered blood in the prehospital setting at the scene. All patients were in hypovolemic shock. Two patients died. Two patients were believed to be unexpected survivors; 1 was predicted by the Trauma and Injury Severity Score, and a second unexpected survivor was a neonate who was in hypovolemic shock and cardiopulmonary arrest. CONCLUSION: The incidence of prehospital use of blood in injured or critically ill children is low. This intervention presented a potential to limit acid-base disturbance, low hemoglobin levels, and coagulopathy in this group. We believe this cohort also contains 2 unexpected survivors.

Evaluation of polymorphic variants in apoptotic genes and their role in susceptibility and clinical progression to systemic lupus erythematosus.

Background Systemic lupus erythematosus (SLE) is an autoimmune disease marked by the disruption of the immune homeostasis. Patients exhibit a wide range of clinical manifestations, and environmental and genetic factors are involved in SLE pathogenesis. Evidence suggests that abnormalities in the cellular and molecular events that coordinate apoptosis may favour the generation of autoantigens involved in autoimmunity. In this way, the apoptotic deregulation may be affected by polymorphic variants in apoptotic-related genes. Methods We analyzed FAS, FASL, BCL-2 and BAX polymorphisms in order to correlate to SLE susceptibility and clinical features. A total of 427 SLE patients from the Hospital de Clínicas de Porto Alegre and 543 controls from southern Brazil were evaluated. Results We observed higher frequencies of the FASL -844CC genotype and -844C allele, as well as of the FASL-844C/IVS2nt-124A haplotype in African-derived SLE patients when compared to controls ( P < 0.001). FASL -844C, which is related to high FasL expression, could contribute to increased apoptosis and to the breakdown of immunological tolerance, favouring autoantibody production and inflammation. On the other hand, the BAX -248GA genotype and the -248A allele , related to low protein expression, were observed as a protective factor against SLE in this same population. The rate of apoptosis and cell death was evaluated in peripheral lymphocytes, and SLE patients presented a higher percentage of dead lymphocytes (CD3+Annexin V+ 7-AAD+) compared to the control group. Conclusion Our data support a role for apoptosis in SLE susceptibility.

Phenomic Approaches and Tools for Phytopathologists.

Plant phenomics approaches aim to measure traits such as growth, performance, and composition of plants using a suite of noninvasive technologies. The goal is to link phenotypic traits to the genetic information for particular genotypes, thus creating the bridge between the phenome and genome. Application of sensing technologies for detecting specific phenotypic reactions occurring during plant-pathogen interaction offers new opportunities for elucidating the physiological mechanisms that link pathogen infection and disease symptoms in the host, and also provides a faster approach in the selection of genetic material that is resistant to specific pathogens or strains. Appropriate phenomics methods and tools may also allow presymptomatic detection of disease-related changes in plants or to identify changes that are not visually apparent. This review focuses on the use of sensor-based phenomics tools in plant pathology such as those related to digital imaging, chlorophyll fluorescence imaging, spectral imaging, and thermal imaging. A brief introduction is provided for less used approaches like magnetic resonance, soft x-ray imaging, ultrasound, and detection of volatile compounds. We hope that this concise review will stimulate further development and use of tools for automatic, nondestructive, and high-throughput phenotyping of plant-pathogen interaction.

Identification of an anti-inflammatory protein from Faecalibacterium prausnitzii, a commensal bacterium deficient in Crohn's disease.

BACKGROUND: Crohn's disease (CD)-associated dysbiosis is characterised by a loss of Faecalibacterium prausnitzii, whose culture supernatant exerts an anti-inflammatory effect both in vitro and in vivo. However, the chemical nature of the anti-inflammatory compounds has not yet been determined. METHODS: Peptidomic analysis using mass spectrometry was applied to F. prausnitzii supernatant. Anti-inflammatory effects of identified peptides were tested in vitro directly on intestinal epithelial cell lines and on cell lines transfected with a plasmid construction coding for the candidate protein encompassing these peptides. In vivo, the cDNA of the candidate protein was delivered to the gut by recombinant lactic acid bacteria to prevent dinitrobenzene sulfonic acid (DNBS)-colitis in mice. RESULTS: The seven peptides, identified in the F. prausnitzii culture supernatants, derived from a single microbial anti-inflammatory molecule (MAM), a protein of 15 kDa, and comprising 53% of non-polar residues. This last feature prevented the direct characterisation of the putative anti-inflammatory activity of MAM-derived peptides. Transfection of MAM cDNA in epithelial cells led to a significant decrease in the activation of the nuclear factor (NF)-κB pathway with a dose-dependent effect. Finally, the use of a food-grade bacterium, Lactococcus lactis, delivering a plasmid encoding MAM was able to alleviate DNBS-induced colitis in mice. CONCLUSIONS: A 15 kDa protein with anti-inflammatory properties is produced by F. prausnitzii, a commensal bacterium involved in CD pathogenesis. This protein is able to inhibit the NF-κB pathway in intestinal epithelial cells and to prevent colitis in an animal model.

Assessment of anti-Müllerian hormone levels in premenopausal patients with systemic lupus erythematosus.

OBJECTIVE: The ovarian reserve of patients with systemic lupus erythematosus (SLE) may be affected by disease activity and medication use. Studies have found that patients with SLE have similar fertility rates as healthy women of the same age. The goal of the present study was to investigate the ovarian reserve of patients with SLE by measuring anti-Müllerian hormone (AMH) levels, and compare it to that of healthy controls. METHOD: This was a case-control study performed on 80 premenopausal women, of whom 40 fulfilled the 1997 American College of Rheumatology (ACR) criteria for SLE and 40 healthy controls paired by oral contraceptive use. Serum concentrations of AMH in peripheral venous blood were measured using a human AMH ELISA kit (CUSABIO, Wuhan, China). RESULTS: AMH serum levels did not differ between patients with SLE and controls (22.79 ± 17.32 ng/ml versus 21.41 ± 16.22 ng/ml, respectively, p = 0.7), even after adjusting for age (21.03 ± 2.074 ng/ml versus 23.97 ± 2.71 ng/ml; p = 0.5). AHM levels were not significantly correlated with disease duration (r = 0.2; p = 0.3), body mass index (r = 0.2; p = 0.2) and disease activity (SLEDAI (r = 0.1; p = 0.7)) and damage indices (SLICC (r = 0.1; p = 0.7)). No associations were found between AMH and ethnicity, current smoking, as well as current or prior use of cyclophosphamide and other immunosuppressants. CONCLUSION: In this cross-sectional study, women with SLE demonstrated similar AMH levels as healthy controls, suggesting preserved ovarian reserve in this population.

Matrix metalloproteinase gene polymorphisms and susceptibility to systemic sclerosis.

The major pathological hallmark of the systemic sclerosis (SSc) is skin and internal organ fibrosis, which results from normal tissue architecture alterations and extracellular matrix (ECM) protein deposition. ECM components are degraded by matrix metalloproteinases (MMP). Promoter region polymorphisms in MMP genes may influence gene expression, resulting in an imbalance between ECM protein production and degradation. Here, we analyzed MMP1 -1607 1G/2G (rs1799750), MMP3 -1171 5A/6A (rs3025058), and MMP9 -1562 C/T (rs3918242) polymorphisms in relation to susceptibility to SSc and its clinical features. The patient group included 98 individuals with longstanding or recently diagnosed disease, meeting the American College of Rheumatology or LeRoy and Medsger criteria for SSc; the control group included 100 healthy blood donors. All participants were of European descent. Genotyping was performed by polymerase chain reaction followed by restriction digestion. Genotype and allele frequencies of MMP polymorphisms were similar between the two groups. In secondary analyses, significantly higher frequency of 1G/2G genotype from MMP1 polymorphism was observed for patients testing positive for antinuclear autoantibodies (P = 0.007), while 1G/1G genotype was associated with interstitial lung disease development (P = 0.018). The 6A/6A genotype from MMP3 polymorphism was absent in patients with calcinosis (P = 0.011), while the MMP3 5A/5A genotype correlated with the presence of anti-topoisomerase I antibodies (P = 0.009) and reduced diffusing capacity for carbon monoxide (P = 0.024). These results suggest that MMP polymorphisms are not associated with SSc susceptibility, although MMP1 and MMP3 variants are associated with specific SSc clinical and laboratory features.

Electroconvulsive therapy as a treatment for refractory neuropsychiatric lupus with catatonia: three case studies and literature review.

Neuropsychiatric disorders associated with systemic lupus erythematosus are very common. Treatment generally consists of glucocorticoids and immunosuppressive therapy; however, some cases are unresponsive. Electroconvulsive therapy (ECT) is a recognized treatment modality in psychiatry and is an option for refractory cases of neuropsychiatric lupus. This report describes three cases of neuropsychiatric lupus that improved with ECT after failure of antipsychotics and immunosuppressive therapy. All cases met DSM-5 criteria for catatonia (case 1: agitation, stereotypies, and grimacing; case 2: stupor, mutism, and grimacing; case 3: agitation, mutism, and stereotypies); therefore, ECT was indicated. This case series shows that ECT can be a therapeutic option in patients with neuropsychiatric lupus, especially when associated with catatonia and unresponsive to conventional treatment.