Asynchronicity of deglacial permafrost thawing controlled by millennial-scale climate variability.

Permafrost is a potentially important source of deglacial carbon release alongside deep-sea carbon outgassing. However, limited proxies have restricted our understanding in circumarctic regions and the last deglaciation. Tibetan Plateau (TP), the Earth's largest low-latitude and alpine permafrost region, remains underexplored.

Reducing the lipase LIPE in mutant α-synuclein mice improves Parkinson-like deficits and reveals sex differences in fatty acid metabolism.

Impaired lipid metabolism is a risk factor for Parkinson's disease (PD) and dementia with Lewy bodies (DLB) and can shift the physiological α-synuclein (αS) tetramer-monomer (T:M) ratio toward aggregation prone monomers. A resultant increase in phospho-serine 129+ αS monomers associating with excess mono- and polyunsaturated fatty acids contributes to the αS aggregation. We previously reported that decreasing the release of monounsaturated fatty acids (MUFAs) by reducing or inhibiting the hormone sensitive lipase (LIPE) reversed pathologic αS phosphorylation and improved soluble αS homeostasis in cultured αS triplication PD neurons and reduced DAergic neurodegeneration in a C.

Generation of G51D and 3D mice reveals decreased α-synuclein tetramer-monomer ratios promote Parkinson's disease phenotypes.

Mutations in the α-Synuclein (αS) gene promote αS monomer aggregation that causes neurodegeneration in familial Parkinson's disease (fPD). However, most mouse models expressing single-mutant αS transgenes develop neuronal aggregates very slowly, and few have dopaminergic cell loss, both key characteristics of PD. To accelerate neurotoxic aggregation, we previously generated fPD αS E46K mutant mice with rationally designed triple mutations based on the α-helical repeat motif structure of αS (fPD E46K→3 K).

Increased palmitoylation improves estrogen receptor alpha-dependent hippocampal synaptic deficits in a mouse model of synucleinopathy.

Parkinson's disease (PD) is characterized by conversion of soluble α-synuclein (αS) into intraneuronal aggregates and degeneration of neurons and neuronal processes. Indications that women with early-stage PD display milder neurodegenerative features suggest that female sex partially protects against αS pathology. We previously reported that female sex and estradiol improved αS homeostasis and PD-like phenotypes in E46K-amplified (3K) αS mice.

Indian Ocean salinity build-up primes deglacial ocean circulation recovery.

The Indian Ocean provides a source of salt for North Atlantic deep-water convection sites, via the Agulhas Leakage, and may thus drive changes in the ocean's overturning circulation. However, little is known about the salt content variability of Indian Ocean and Agulhas Leakage waters during past glacial cycles and how this may influence circulation. Here we show that the glacial Indian Ocean surface salt budget was notably different from the modern, responding dynamically to changes in sea level.

Early surgery? In-house mortality after proximal femoral fractures does not increase for surgery up to 48 h after admission.

Purpose: The economic cost linked to the increasing number of proximal femur fracture and their postoperative care is immense. Mortality rates are high. As early surgery is propagated to lower mortality and reduce complication rates, a 24-h target for surgery is requested.

The Parkinson-Associated Toxin Paraquat Shifts Physiological α-Synuclein Tetramers toward Monomers That Can Be Calpain-Truncated and Form Oligomers.

Abnormal aggregation of α-synuclein (αS) is thought to initiate neuronal dysfunction and death in Parkinson disease (PD). In addition to higher-molecular-weight, oligomeric, and polymeric forms of αS associated with neurotoxicity and disease, recent findings indicate the occurrence of physiological tetrameric assemblies in healthy neurons in culture and in brain. Herein, the PD-associated neurotoxin paraquat reduced physiological tetramers and led to calpain-truncated monomers and an approximately 70-kDa apparent oligomer different in size from physiological αS multimers.

Concomitant fractures in patients with proximal femoral fractures lead to a prolonged hospital stay but not to increased complication rates or in-house mortality if treated surgically: a matched pair analysis.

Background: Impact of concomitant fractures on patients sustaining a proximal femur fracture remains unclear. Rising numbers and patient need for rehab is an important issue. The objective of our study was to investigate the impact of concomitant fractures, including all types of fractures, when treated operatively, for proximal femur fractures on the length of hospital stay, in-house mortality and complication rate.

Dynamic physiological α-synuclein S129 phosphorylation is driven by neuronal activity.

In Parkinson's disease and other synucleinopathies, the elevation of α-synuclein phosphorylated at Serine129 (pS129) is a widely cited marker of pathology. However, the physiological role for pS129 has remained undefined. Here we use multiple approaches to show for the first time that pS129 functions as a physiological regulator of neuronal activity.

Anticoagulants and fracture morphology have a significant influence on total blood loss after proximal femur fractures.

Introduction: Blood loss after proximal femoral fractures is an important risk factor for postoperative outcome and recovery. The purpose of our study was to investigate the total blood loss depending on fracture type and additional risks, such as anticoagulant use, to be able to recognize vulnerable patients depending on planned surgery and underlying comorbidities.

Materials And Methods: A retrospective single center study including 1478 patients treated operatively for a proximal femoral fracture between January 2016 and June 2020 at a level I trauma center.

Do anticoagulants impact the "in-house mortality" after surgical treatment of proximal femoral fractures-a multivariate analysis.

Purpose: The prevalence of proximal femur fractures is increasing with rising population age. Patients are presenting with more comorbidities. Anticoagulants create a challenge for the necessary early surgical procedure (osteosynthesis or arthroplasty).

Does tranexamic acid reliably reduce blood loss in proximal femur fracture surgery?

Purpose: The aim of our study was to investigate the use of tranexamic acid in patients with proximal femoral fractures and compare the total blood loss, transfusion rates, complications, and the application method.

Methods: A retrospective single center cohort study (level I trauma center) with 1479 patients treated operatively for a proximal femoral fracture between January 2016 and June 2020 was performed. 1 g of tranexamic acid was applied (systemic, topic or combined application).

A Brain-Penetrant Stearoyl-CoA Desaturase Inhibitor Reverses α-Synuclein Toxicity.

Increasing evidence has shown that Parkinson's disease (PD) impairs midbrain dopaminergic, cortical and other neuronal subtypes in large part due to the build-up of lipid- and vesicle-rich α-synuclein (αSyn) cytotoxic inclusions. We previously identified stearoyl-CoA desaturase (SCD) as a potential therapeutic target for synucleinopathies. A brain-penetrant SCD inhibitor, YTX-7739, was developed and has entered Phase 1 clinical trials.

Pathogenic Mechanisms of Cytosolic and Membrane-Enriched α-Synuclein Converge on Fatty Acid Homeostasis.

α-Synuclein (αS) plays a key role in Parkinson's disease. Although Parkinson's disease is typically "sporadic," inherited αS missense mutations provide crucial insights into molecular mechanisms. Here, we examine two clinical mutants, E46K and G51D, which are both in the conserved N-terminus that mediates transient αS-membrane interactions.

A minimally invasive cerclage of the tibia in a modified Goetze technique: operative technique and first clinical results.

Introduction: In spiral fractures of the tibia, the stability of an osteosynthesis may be significantly increased by additive cerclages and, according to biomechanical studies, be brought into a state that allows immediate full weight bearing. As early as 1933, Goetze described a minimally invasive technique for classic steel cerclages. This technique was modified, so that it can be used for modern cable cerclages in a soft part saving way.

Midterm follow-up of elderly patients with fragility fractures of the pelvis: A prospective cohort-study comparing operative and non-operative treatment according to a therapeutic algorithm.

Introduction: The treatment of fragility fractures of the pelvis (FFP) is a challenge. The variations of non-operative- and of operative treatment are manifold and a structured treatment algorithm is lacking. The purpose of this study was to evaluate the outcome of elderly patients with a FFP who were treated with a therapeutic algorithm based on the FFP-classification.

Wild-type GBA1 increases the α-synuclein tetramer-monomer ratio, reduces lipid-rich aggregates, and attenuates motor and cognitive deficits in mice.

Loss-of-function mutations in acid beta-glucosidase 1 (GBA1) are among the strongest genetic risk factors for Lewy body disorders such as Parkinson's disease (PD) and Lewy body dementia (DLB). Altered lipid metabolism in PD patient-derived neurons, carrying either GBA1 or PD αS mutations, can shift the physiological α-synuclein (αS) tetramer-monomer (T:M) equilibrium toward aggregation-prone monomers. A resultant increase in pSer129+ αS monomers provides a likely building block for αS aggregates.

Altered conformation of α-synuclein drives dysfunction of synaptic vesicles in a synaptosomal model of Parkinson's disease.

While misfolding of alpha-synuclein (αSyn) is central to the pathogenesis of Parkinson's disease (PD), fundamental questions about its structure and function at the synapse remain unanswered. We examine synaptosomes from non-transgenic and transgenic mice expressing wild-type human αSyn, the E46K fPD-causing mutation, or an amplified form of E46K ("3K"). Synaptosomes from mice expressing the 3K mutant show reduced Ca-dependent vesicle exocytosis, altered synaptic vesicle ultrastructure, decreased SNARE complexes, and abnormal levels of certain synaptic proteins.

A Stearoyl-Coenzyme A Desaturase Inhibitor Prevents Multiple Parkinson Disease Phenotypes in α-Synuclein Mice.

Objective: Parkinson disease (PD) has useful symptomatic treatments that do not slow the neurodegenerative process, and no significant disease-modifying treatments are approved. A key therapeutic target in PD is α-synuclein (αS), which is both genetically implicated and accumulates in Lewy bodies rich in vesicles and other lipid membranes. Reestablishing αS homeostasis is a central goal in PD.

Female Sex and Brain-Selective Estrogen Benefit α-Synuclein Tetramerization and the PD-like Motor Syndrome in 3K Transgenic Mice.

Many studies report a higher risk for Parkinson's disease (PD) and younger age of onset in men. This, and the fact that the neuropathological process underlying PD symptoms may begin before menopause, suggests that estrogen-based hormone therapy could modify this higher risk in males. However, the effects of female sex or estrogen on α-synuclein (αS) homeostasis and related PD neuropathology remain unknown.

[Three-point buttressing with internal fixator for minimally invasive stabilization of the anterior pelvic ring : Operative technique and first clinical results].

Background: The changing age distribution in society inevitably leads to a percentage increase in osteoporotic and fatigue fractures as well as the absolute number of insufficiency fractures of the pelvic ring. Due to pain these fractures lead to a loss of mobility and autonomy. To prevent these consequences surgical treatment is increasingly being performed.

Lipidomic Analysis of α-Synuclein Neurotoxicity Identifies Stearoyl CoA Desaturase as a Target for Parkinson Treatment.

In Parkinson's disease (PD), α-synuclein (αS) pathologically impacts the brain, a highly lipid-rich organ. We investigated how alterations in αS or lipid/fatty acid homeostasis affect each other. Lipidomic profiling of human αS-expressing yeast revealed increases in oleic acid (OA, 18:1), diglycerides, and triglycerides.

Attenuated impression of irony created by the mismatch of verbal and nonverbal cues in patients with autism spectrum disorder.

Perception of irony has been observed to be impaired in adults with autism spectrum disorder. In typically developed adults, the mismatch of verbal and nonverbal emotional cues can be perceived as an expression of irony even in the absence of any further contextual information. In this study, we evaluate to what extent high functioning autists perceive this incongruence as expressing irony.