Molecular and physiologic changes in the SpaceX Inspiration4 civilian crew.

Human spaceflight has historically been managed by government agencies, such as the NASA Twins Study1, but new commercial spaceflight opportunities have opened spaceflight to a broader population. In 2021, the SpaceX Inspiration4 mission launched the first-ever all civilian crew to low Earth orbit, which included the youngest American astronaut (age 29), novel in-flight experimental technologies (handheld ultrasound imaging, smartwatch wearables, and immune profiling), ocular alignment measurements, and new protocols for in-depth, multi-omic molecular and cellular profiling. Here we report the primary findings from the 3-day spaceflight mission, which induced a broad range of physiological and stress responses, neurovestibular changes indexed by ocular misalignment, and altered neurocognitive functioning, some of which match long-term spaceflight2, but almost all of which did not differ from baseline (pre-flight) after return to Earth. Overall, these preliminary civilian spaceflight data suggest that short-duration missions do not pose a significant health risk, and moreover present a rich opportunity to measure the earliest phases of adaptation to spaceflight in the human body at anatomical, cellular, physiologic, and cognitive levels. Finally, these methods and results lay the foundation for an open, rapidly expanding biomedical database for astronauts3, which can inform countermeasure development for both private and government-sponsored space missions.

Probing insulators under pressure.

Applying pressure on a material can reveal many physical properties and is a very efficient tool to understand its physics. Resistivity measurements have been the ideal probe to study metals under pressure. However, in the case of insulators, resistivity, or conductivity, it is often not the appropriate quantity characterizing the material. In this work, we present a newly developed in situ pressure tuning system that can be used over a wide temperature range (2 K-300 K) and allows changing the pressure at any temperature. We also present AC calorimetry and capacitance/loss measurements under pressure and demonstrate how this combination can be used to characterize a material that is too insulating for standard resistivity techniques.

Complexation of ß-cyclodextrin with dual molecular probes bearing fluorescent and paramagnetic moieties linked by short polyether chains.

Electron paramagnetic resonance (EPR) and fluorescence spectroscopies provide molecular-level insights on the interaction of paramagnetic and fluorescent species with the microenvironment. A series of dual molecular probes bearing fluorescent and paramagnetic moieties linked by flexible short polyether chains have been synthesized. These new molecular probes open the possibility to investigate various multi-component systems such as host-guest systems, polymeric micelles, gels and protein solutions by using EPR and fluorescence spectroscopies concertedly. The EPR and fluorescence spectra of these compounds show that the dependence of the rotational correlation time and fluorescence quantum yield on the chain length of the linker is not linear, due to the flexibility of the polyether linker. The quenching effect of the nitroxide moiety on the fluorescence intensity of the pyrene group varies with the linker length and flexibility. The interaction of these dual molecular probes with ß-cyclodextrin, in solution and in polymeric gels, was evaluated and demonstrated by analysis of EPR and fluorescence spectra.

Diversity of Flea (Siphonaptera) Parasites on Red Foxes (Vulpes vulpes) in Romania.

Red foxes (Vulpes vulpes (L.)) are widespread across Europe, tolerant of synanthropic ecosystems, and susceptible to diseases potentially shared with humans and other animals. We describe flea fauna on red foxes in Romania, a large, ecologically diverse country, in part because fleas may serve as an indicator of the risk of spillover of vector-borne disease. We found 912 individual fleas of seven species on the 305 foxes assessed, for an infestation prevalence of 49.5%. Mean flea load per fox was 5.8 (range 0-44 fleas), and flea detections were most abundant in fall and early spring. Fleas included generalists (Ctenocephalides canis (Curtis), 32.6% of all fleas), Ct. felis (Bouché, 0.1%), and Pulex irritans L. (29.9%), the fox specialist Chaetopsylla globiceps (Taschenberg, 32.5%), mesocarnivore fleas Paraceras melis Walker (3.2%) and Ch. trichosa Kohaut (1.5%), and the small mammal flea Ctenophthalmus assimilis (Taschenberg, 0.1%), which is rarely or never reported from carnivores. There were significantly more female than male Ch. globiceps, Ct. canis, and Pu. irritans, and these three species were the most broadly distributed geographically. Diversity indices suggested reduced diversity in mountainous areas above 700 m. When compared to other flea studies on foxes in Europe, Romania had flea diversity near the median of reports, which was unexpected given Romania's high ecological diversity. Notably absent prey specialists, compared to other studies, include Archaeopsylla erinacei (Bouché) and Spilopsyllus cuniculi (Dale). Further studies of possible disease agents in fox fleas could help elucidate possible risks of vector-borne disease in foxes, domestic animals, and humans as well.

Neonatal Anaplasma platys infection in puppies: Further evidence for possible vertical transmission.

Anaplasma platys, the aetiological agent of infectious canine cyclic thrombocytopaenia, infects platelets of dogs, usually causing mild or asymptomatic disease. Although A. platys is transmitted by ticks, as for other Anaplasma species, alternative modes of transmission may be involved. The aim of the present study was to evaluate the occurrence of A. platys infection in litters of puppies, which could suggest possible vertical transmission. Twelve litters, together with the respective bitches, were included in the study for the detection of A. platys DNA by PCR, followed by sequencing. Five puppies, from 2/4 litters <28 days of age, tested positive for A. platys DNA. No puppies from eight litters 1-3 months of age tested positive for A. platys DNA. The identical sequences (16S rRNA and gltA partial gene), the absence of ticks on puppies at the time of collection and the young age of the five infected puppies suggest vertical transmission of A. platys. This mode of transmission might contribute to the maintenance and spread of the pathogen in canine populations.

Occurrence of ticks in the subcutaneous tissue of red foxes, Vulpes vulpes in Czech Republic and Romania.

An extensive survey of parasites in red foxes (Vulpes vulpes) was independently conducted in Romania and the Czech Republic. Carcasses were examined by necropsy, and small, dark nodules apparently containing ticks were noticed in the subcutaneous tissue of several foxes. Histopathological examination was performed using hematoxylin and eosin (HE) staining. Of the 91 foxes examined from the Czech Republic, 14 (15.4%) were harboring ticks in the subcutaneous tissue. In the majority of these cases, 1-3 nodules/fox were found, with a maximum of 31 nodules/fox. In Romania a single examined fox had subcutaneous ticks. All ticks collected from subcutaneous tissue were partially engorged adults. Based on morphological features, Ixodes ricinus, I. hexagonus, I. crenulatus and Dermacentor reticulatus were identified. The histopathological examination revealed chronic granulomatous panniculitis with peripheral fibrosis and intralesional presence of the ticks. Only few data are available regarding ticks localized in the subcutaneous tissue of any host. All the ticks were dead or already decomposed and it is evident that subcutaneous location does not represent an evolutionary advantage, as the detachment and finishing the life cycle is impossible.

Efficacy and safety of CDX-301, recombinant human Flt3L, at expanding dendritic cells and hematopoietic stem cells in healthy human volunteers.

Fms-like tyrosine kinase-3 ligand (Flt3L) uniquely binds the Flt3 (CD135) receptor expressed on hematopoietic stem cells (HSCs), early progenitor cells, immature thymocytes and steady-state dendritic cells (DCs) and induces their proliferation, differentiation, development and mobilization in the bone marrow, peripheral blood and lymphoid organs. CDX-301 has an identical amino-acid sequence and comparable biological activity to the previously tested rhuFlt3L, which ceased clinical development over a decade ago. This Phase 1 trial assessed the safety, pharmacokinetic, pharmacodynamic and immunologic profile of CDX-301, explored alternate dosing regimens and examined the impact of rhuFlt3L on key immune cell subsets. Thirty healthy volunteers received CDX-301 (1-75 µg/kg/day) over 5-10 days. One event of Grade 3 community-acquired pneumonia occurred. There were no other infections, dose-limiting toxicities or serious adverse events. CDX-301 resulted in effective peripheral expansion of monocytes, hematopoietic stem and progenitor cells and key subsets of myeloid DCs and plasmacytoid DCs, with no clear effect on regulatory T cells. These data from healthy volunteers support the potential for CDX-301, as monotherapy or in combination with other agents, in various indications including allogeneic HSC transplantation and immunotherapy, but the effects of CDX-301 will need to be investigated in each of these patient populations.

Coherent frequency conversion in a superconducting artificial atom with two internal degrees of freedom.

By adding a large inductance in a dc-SQUID phase qubit loop, one decouples the junctions' dynamics and creates a superconducting artificial atom with two internal degrees of freedom. In addition to the usual symmetric plasma mode (s mode) which gives rise to the phase qubit, an antisymmetric mode (a mode) appears. These two modes can be described by two anharmonic oscillators with eigenstates |ns> and |na> for the s and a mode, respectively. We show that a strong nonlinear coupling between the modes leads to a large energy splitting between states |0s,1a> and |2s,0a>. Finally, coherent frequency conversion is observed via free oscillations between the states |0s,1a> and |2s,0a>.

[Multiple splenic abscesses associated with normotensive hydrocephaly]. / Abcese splenice multiple asociate cu hidrocefalia adultului.

The paper contains a concise review of the current literature on the splenic abscesses and presents an unusual association of multiple splenic abscesses with normotensive hydrocephaly to an elderly patient, treated by ventriculo-cardiac shunting and splenectomy as an one stage procedure performed by a combined surgical team (neurosurgeon, vascular surgeon and general surgeon), with a favourable outcome. As far as the authors know, this is the first communication of multiple splenic abscesses associated with adult hydrocephaly treated by a simultaneous surgical approach.

[Roman medical instruments from Lower Moesia]. / Instruments medicaux romains provenus de la province Mísie inférieure.

To elucidate the evolution of society over time, ancient medicine is a very interesting and important researching field. Archaeological discoveries, such as the objects described by this article, but other ancient sources, also, are able to provide a complex framework of medical practice in Roman times. The geographic area that we have like target in this material is the province of Lower Moesia, which includes the territory between Danube and Black Sea (Romanian Dobrodja) and northern Bulgaria. In the present study we present nine ancient medical instruments, from a private collection: two tweezers, two ear probes, a probe-spatula, a probe-spoon, a spoon for pharmacy and two fragments of some kind of hooks used in surgical operations. Most likely, we have a mixed medical kit with tools used in general medicine, surgery, in preparation of the pharmaceutical treatments, but very possible, also, in cosmetic practices. Publication of these archaeological materials is, in addition to an extra page in the history of ancient medicine, a pretext for stepping up in a research field that, in other regions of the former Roman Empire, it is a great interest for researchers.

The place of local/regional perforator flaps in complex traumas of the forearm.

BACKGROUND: Our aim was to conduct a retrospective study regarding the advantages of doing the all-in-one reconstruction in the same step with the debridement, and the possibility of using the local/regional perforator flaps to cover the tissue defects. METHODS: We reviewed a series of 137 cases from 1999 until now, for acute traumas with tissue defects of the forearm. We performed a regional perforator flap in 16 cases, and a local perforator flap in 121 cases. These flaps were used for both simple and complex defects coverage, including 26 cases with fractures and devascularization. RESULTS: The follow-up was between 2 months and 2 years. In all the cases the extremity was salvaged and an useful functional recovery was obtained. A very good evolution, with complete survival of the flap was recorded in 133 cases. We completely lost only one flap, and registered minor complications in three cases. CONCLUSION: The local perforator flaps represent a good and safe indication for small and medium defects in the forearm.

Relapses in patients with idiopathic vasculitis: diagnostic difficulties.

Idiopathic vasculitis are complex inflammatory diseases that affect small, medium and large sized vessels. The disease recurrence, or relapse, which frequently characterizes the vasculitis course, raises the morbidity and mortality in vasculitic patients. Relapse diagnosis is currently a difficult clinical problem, since the original vasculitis presentation may change during relapse, in some cases even to a more aggressive form. Furthermore, relapse may overlap "damage" syndromes and subclinical active lesions can occur in asymptomatic patients. We focus here on certain organ-specific and systemic manifestations associated to relapse, also presenting unusual and unexpected features of relapse in various vasculitic conditions. Assessment of disease activity to diagnose relapse, including serologic markers associated to or predicting relapse, and relapse diagnosis in subclinical vasculitis are also discussed.

Study of chemotactic activity developed by neutrophils from rheumatoid arthritis patients.

Neutrophils are the predominant cells accumulated in the synovial fluid (SF) of rheumatoid arthritis (RA) patients. Accumulation of neutrophils may be regarded as a possible way by which neutrophils exert cytotoxic functions. The aim of the present study was to analyze the chemotactic response of neutrophils (PMNs) isolated from the peripheral blood or SF of patients with RA by performing the chemotaxis assay, in which N-formyl-methionyl-leucyl-phenylalanine (FMLP) was used as chemotactic agent. Our results showed that FMLP induced response of peripheral blood neutrophils from 12 patients with RA was similar with the response of 15 healthy controls. A decreased chemotactic response to FMLP was, however, observed in PMNs isolated from the SF of RA patients as comlipared with peripheral blood cells. Therefore, this defective chemotactic ability of neutrophil, was inversely correlated with the number of infiltrating cells in SF. These results indicate that chemotactic ability of neutrophils may be reduced after migration to the SF. Because PMNs chemotaxis in vivo has likely occurred in the presence of serum or SF, we tried to simulate the same conditions in vitro. Therefore, we analyzed the effect of serum or SF on the RA-PMNs chemotaxis. Heat-inactivated serum produced a marked reduction of chemotactic activity developed by PMNs isolated from patients with RA. Notably, a significant increase of chemotactic activity was observed when FMLP and serum stimuli were used together, as compared with the same stimuli used alone. The results suggested that complement activation might interfere with neutrophils chemotaxis. SF amplifies the chemotactic activity of PMNs isolated from peripheral blood of RA patients, but does not affect the chemotaxis developed by PMNs isolated from SF. The data might suggest that several components of SF (IL-8, leukotrien B4, thrombin, platelet-activating factor, etc.) could serve as a potent stimulus for recruitment of neutrophils from periphery into the RA joint. In conclusion, serum or SF components seem to contribute to chemotaxis of neutrophils and play a role in differential killing of PMNs and incidence of infection.

Cytokine patterns and pathogenicity in autoimmune diseases.

Cytokines are a large family of small proteins secreted by leukocytes and having an essential role in mediating the immune function. Many cytokines have multiple cellular sources and targets, as well as many natural inducers and inhibitors. These features and moreover the functional particularities of cytokines (autocrine and paracrine mode of action, overlapped activities, pleiotropic action, functioning as a complex regulatory network, and reciprocal down-regulation of the Th1 and Th2 cytokine groups) hampered the investigation of cytokines' role in autoimmune diseases (ADs). Despite this, the experimental and clinical studies have firmly documented the implication of cytokines in major pathophysiological and pathogenetic mechanisms associated with both the acute (onset and/or recurrence) and the chronic stages of ADs. The enhanced production of cytokines during the acute phase of systemic lupus erythematosus, rheumatoid arthritis and vasculitis has pathogenic effects such as appearance of anti-neutrophil cytoplasmic antibodies, initiation of vascular thrombosis and/or an increased production of autoantigens. The potent proinflammatory cytokines IL-1 and TNFalpha and also IL-8 and IFNalpha,gamma stimulate cells in different tissues to release harmful proteinases and reactive oxygen species, contributing to tissue damage. Some correlations have been found between serum cytokine levels and disease activity in certain systemic ADs. Studies investigating the cytokine pattern in ADs revealed the prevalence of the proinflammatory Th1-type cytokines in the target organ of patients with organ-specific ADs, such as multiple sclerosis and autoimmune thyroid disease, and heterogeneous cytokine profiles in patients with systemic ADs. A lot of factors, including the mechanism of tissue damage, the type of antigen-presenting cells and costimulatory molecules, and also the hormonal status, favor secretion of cytokines of Th1- or Th2-type in these patients. Beneficial effects have been obtained in patients with rheumatoid arthritis and Crohn disease by administering biotechnologically manufactured anti-TNFalpha antibodies or TNFalpha receptors. The risks of these cytokine-targeting therapeutical interventions are also discussed.

Somatic frameshift mutations in the Bloom syndrome BLM gene are frequent in sporadic gastric carcinomas with microsatellite mutator phenotype.

BACKGROUND: Genomic instability has been reported at microsatellite tracts in few coding sequences. We have shown that the Bloom syndrome BLM gene may be a target of microsatelliteinstability (MSI) in a short poly-adenine repeat located in its coding region. To further characterize the involvement of BLM in tumorigenesis, we have investigated mutations in nine genes containing coding microsatellites in microsatellite mutator phenotype (MMP) positive and negative gastric carcinomas (GCs). METHODS: We analyzed 50 gastric carcinomas (GCs) for mutations in the BLM poly(A) tract aswell as in the coding microsatellites of the TGFbeta1-RII, IGFIIR, hMSH3, hMSH6, BAX, WRN, RECQL and CBL genes. RESULTS: BLM mutations were found in 27% of MMP+ GCs (4/15 cases) but not in any of the MMP negative GCs (0/35 cases). The frequency of mutations in the other eight coding regions microsatellite was the following: TGFbeta1-RII (60 %), BAX (27%), hMSH6 (20%),hMSH3 (13%), CBL (13%), IGFIIR (7%), RECQL (0%) and WRN (0%). Mutations in BLM appear to be more frequently associated with frameshifts in BAX and in hMSH6and/or hMSH3. Tumors with BLM alterations present a higher frequency of unstable mono- and trinucleotide repeats located in coding regions as compared with mutator phenotype tumors without BLM frameshifts. CONCLUSIONS: BLM frameshifts are frequent alterations in GCs specifically associated with MMP+tumors. We suggest that BLM loss of function by MSI may increase the genetic instability of a pre-existent unstable genotype in gastric tumors.

Lectin-binding profile of serum IgA in women suffering from systemic autoimmune rheumatic disorders.

In many pathological states changes in the carbohydrate part of serum glycoproteins occur, the etiopathogenic role or diagnosis significance of these abnormally glycosylated glycoproteins being relevant in many instances. The aim of this study was to determine the glycosylation pattern of the serum immunoglobulin A (IgA) in young women suffering from systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), by comparison with that in healthy ones. We used lectin proteins as bivalent reagents to selectively and specifically recognize and bind the different oligosaccharides at the surface of the IgA molecules and precipitate them. The serum IgA level in the SLE and RA women included in this study was of 4 and respectively 6 times greater than in control women. Our experiments revealed for the IgA isolated from SLE women a very low degree of glycosylation, as follows: in the Fc region, we detected a markedly reduced level of the unbisected, biantennary oligosaccharides (by 72.8%) and of the unbisected, tri- and tetraantennary oligosaccharides (by 40%), accompanied by a slightly increased level of the bisected (by 14.7%) and fucosylated (by 13.3%) oligosaccharides; in the hinge region, a marked degalactosylation (by 74.4%) of the oligosaccharides was revealed; the sialylation degree of the IgA molecules was thus reduced by 71.2%. Related to it, it is reasonable to presume a certain role of the degalactosylated IgA fraction in renal tissue deposition of IgA in SLE patients, as it has been ascribed to this fraction in IgA nephropathy. Referring to the IgA isolated from RA women, we showed that it selectively bound the lectins, but lacked the property to be lectin-precipitated, most probably due to an altered arrangement of the oligosaccharide chains at the surface of the glycoprotein.

p56lck activity and expression in peripheral blood lymphocytes from patients with systemic lupus erythematosus.

In this study we analyzed the activity and the expression of p56lck protein tyrosine kinase in peripheral blood lymphocytes (PBLs) from systemic lupus erythematosus (SLE) patients and from healthy donors. The p56lck activity, determined by a non-radioactive Tyrosine Kinase Assay Kit, was significantly higher in active SLE PBLs and discriminated this group of patients from inactive SLE patients (p = 0.002) and healthy donors (p = 0.009). p56lck level decreased in SLE lymphocytes (especially for inactive SLE lymphocytes, p = 0.005) when compared to healthy donors. These differences were also reflected by the specific activity of p56lck that was clearly elevated in active SLE lymphocytes when compared to inactive SLE (p = 0.022) or healthy donors lymphocytes (p = 0.006). A positive correlation between the activity of p56lck and the tyrosine phosphorylation level in active SLE lymphocytes was found.

Treatment with alpha-interferon in chronic hepatitis.

The treatment of chronic viral hepatitis with Interferon has been introduced in clinical practice over the past decade an represents an important step in the management of those diseases. The data existing in literature are conflicting about the dose and period of treatment with Interferon, many treatment schedules being proposed. There are also a lot of markers used or proposed to be used to determine the response to treatment, their predicting efficacy being largely studied. The response to alpha-Interferon in a standard 6 month regimen in chronic hepatitis B, chronic hepatitis C and chronic hepatitis B and C is studied; alanine-aminotransferase (ALAT) and aspartate-aminotransferase (ASAT) are the markers used to determine the response to treatment.