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The development and diversification of sensory proprioceptive neurons, which reside in the dorsal root ganglia (DRG) and express the tropomyosin receptor kinase C (TrkC), depend on the transcription factor (TF) Runx3. Runx3-deficient mice develop severe limb ataxia due to TrkC neuron cell death. Two additional TFs Pou4f1 (also called Brn3a) and Isl1 also play an important role in sensory neuron development. Thus, we aimed to unravel the chromatin state of early-developing TrkC neurons and decipher the Runx3 high-confidence target genes (HCT) and the possible cooperation between Runx3, Brn3a and Isl1 in the regulation of these genes. Runx3 expression is driven by the gene proximal P2 promoter. Transcriptome analysis was conducted by RNA-seq on RNA isolated from heterozygous (P2+/-) vs. homozygous (P2-/-) TrkC neurons and differentially expressed genes (DEGs) were determined. Genome-wide occupancy of Runx3, Brn3a, Isl1 and histone H3 acetylated on lysine 27 (H3K27Ac) was determined using CUT&RUN. The landscape of Transposase-accessible chromatin was analyzed via ATAC-seq. The intersection of Runx3 genomic occupancy-associated genes and DEG data discovered 244 Runx3 HCT. Brn3a and Isl1 were found to bind to numerous genomic loci, some of which overlapped with Runx3. Most genomic regions bound by each of these three TFs or co-bound by them resided in distantly located enhancer regions rather than in gene promoters. In activated and suppressed neuronal Runx3 HCT, Runx3 cooperated mainly with Brn3a to regulate expression through distantly located enhancers. Interestingly, suppression of non-neuronal immune genes was mainly managed via Runx3 without Brn3a. The distribution of ATAC and H3K27Ac marked regions in Runx3 peaks containing at least one RUNX binding site (Runx3_RBS) revealed that while most promoter regions were marked by ATAC, a prominent fraction of intron/intergenic regions occupied by Runx3, Brn3a or Isl1 were unmarked by ATAC and/or H3K27Ac. These analyses shed new light on the interplay of Runx3, Brn3a, Isl1, and open chromatin regions in regulating the Runx3 HCT in the early developmental stages of TrkC neurons.

This study examines the Roman burgus and medieval lowland castle ‘Zullestein’ near Biblis (Bergstraße district/Hessen/Germany) and its surrounding fluvio-scape. The aim of the study is to reassess the appearance of the fortifications and the surrounding area at the confluence of the River Weschnitz and the River Rhine based on the excavation results from the 1970s and current geoarchaeological research on site. Our approach encompasses electrical resistivity tomography, direct push sensing, sediment coring and the use of a high-resolution digital elevation model in combination with historical depictions of the Zullestein site from the 17th century AD. The findings of this integrative approach indicate that the Roman fort was likely located at a secondary channel of the River Rhine. With the renewed occupation of the Zullestein site by Lorsch Abbey during Carolingian times and the expansion into a lowland castle in the 11th century, the site was now located at the Weschnitz mouth into the Rhine, likely as part of anthropogenic interventions related to the Weschnitz fluvioscape. Traces of the final phase of the castle at the time of the Thirty Years’ War can still be seen in the terrain today and their attribution to individual elements of the historical account can be confirmed by the geoarchaeological results. The combination of methods presented in this study is a suitable option if excavations are not possible.

The ancient site of Olympia is located on the northern fringe of the Basin of Makrisia at the confluence of the Kladeos and Alpheios rivers (western Peloponnese, Greece) and was used as a venue for the Panhellenic Games from Archaic times until the 4th century AD. Geophysical prospection (frequency domain electromagnetic induction and electrical resistivity tomography) was carried out as a basis for detailed geoarchaeological investigations. In doing so, we identified a previously unknown building structure adjacent to the Altis, the inner part of the sanctuary at Olympia. Situated south of the Southwest Thermae, this structure measures at least 100 m (WSW-ENE) by 80 m (NNW-SSE). Its external orientation is in line with the orientation of the Southwest Thermae and the Leonidaion. We retrieved sediment cores from 17 different locations in combination with high-resolution direct push sensing from inside the newly found structure. All cores revealed distinct units of organic-rich limnic sediments dominated by clay and fine silt. Geochemical and micropaleontological analyses of selected sediment samples indicate highly eutrophic conditions, as evidenced by elevated phosphorous concentrations and the dominance of the ostracod species Cyprideis torosa, which is able to live under low-oxygen conditions. Moreover, molecular biomarker analyses show a significant input of lipid fecal markers, implying strong anthropogenic pollution. Further, the limnic sediments include numerous charcoal remains and abundant diagnostic artifacts such as ceramic fragments and building material. Radiocarbon dating documents that these limnic conditions persisted within the building structure from at least the 5th century BC to the 6th century AD. The identified building structure lies in the immediate proximity to the Lake of Olympia, which was recently found to have existed from the mid-Holocene to the Medieval period. Its characteristic filling with fine-grained sediments and multiple indications for a strongly polluted and heavily used standing water environment let us hypothesize that it was possibly used as a harbor installation. A harbor at ancient Olympia could have been used to reach the sanctuary by boat and to transport goods of all kinds.

Today’s fluvioscape of the Hessische Ried (Upper Rhine Graben) is the consequence of human intervention on the natural drainage system that has transformed a large floodplain into an intensively used cultural landscape. Already, the Romans carried out river regulation and water management to guarantee the transportation of material and troops, securing the territory of the Roman Empire. To secure the so-called Rhein-Limes, burgi (fortlets) were constructed along small tributaries of the River Rhine under Valentinian I. (364–375). The burgus at Trebur-Astheim represents such a military site. It is located at the Schwarzbach/Landgraben fluvial system, which was actively used as a waterway and connected important military sites such as the castra “Auf Esch” (Groß-Gerau) with the River Rhine and, thus, with the provincial capital Mogontiacum (Mainz). Using a combination of magnetic gradiometry, frequency domain electromagnetic induction (FDEMI), electrical resistivity tomography (ERT), direct push-sensing (DP), and sediment coring, we were able to detect a 15 m wide and 2.5 m deep Roman canal between the burgus at Trebur-Astheim and the River Rhine, opening the Hessische Ried hinterland to wider trade routes. Radiocarbon dating further reveals that after a final re-excavation, the channel started to silt up in the 7th/8th century AD and finally fell out of use. This last period of use may be associated with the activities of the Carolingian Königspfalz (royal palace) Trebur. Our study shows that the fluvioscape of the Hessische Ried dates back to Roman times and that the canal at Trebur-Astheim is one of the few navigable canals known to have existed north of the Alps during the Roman period and the Early Middle Ages.

The artificial historical Lake Lorsch (1474/1479 to 1718/1720 CE) in the northeastern Upper Rhine Graben (Germany) is known from various historical sources (e.g., for fish farming) as a significant anthropogenic imprint of the Weschnitz floodplain. Nevertheless, there have been no geomorphological and sedimentological investigations into the (quasi-)natural context for the creation of the lake, its importance as a potential sediment archive and the subsequent use of the lake area until modern times. No relics of the lake can be observed in today's landscape. We investigated the geomorphological setting of the area using a high-resolution digital elevation model, groundwater-level data, and geophysical prospection, as well as sedimentological information from four sediment cores. Results indicate that the location of the lake is topographically deeper in relation to its receiving waters of the old Weschnitz and that Lake Lorsch was fed by groundwater. Sedimentary analysis (core LOR 21A, unit 2; LOSE 4 and LOSE 5, unit 3) exhibits lake deposit, with characteristics indicative of a limnic environment and a high groundwater table. At the same time, adjacent stratigraphy shows channel deposits (core LOR 20A, unit 3), reflecting an anthropogenically controlled inflow via a channel (Renngraben). Our results, based on a relative elevation model, fit well with the historical records: that the inflow for the anthropogenic channel was via the old Weschnitz (topographically higher than the lake area) and that the artificial Landgraben canal (topographically lower than the lake area) was crossed by a water bridge. It is a good example of how humans have acted as fluvial- and water-related agents for at least 500 years in the Weschnitz floodplain.

Intensive human intervention in the natural drainage system of the Hessische Ried (Upper Rhine Graben, Germany) resulted in the transformation of a large wetland into an intensively used cultural landscape. At least since the first century CE, when Romans conducted early river regulation and water management, the natural water network has experienced extensive anthropogenic re-organisation. The LandGraben project focuses on the reconstruction of the natural and anthropogenic watercourse systems along the river Landgraben, a tributary to the river Rhine in the northern Hessische Ried. Several rivers from the southern Hessische Ried could have fed the river Landgraben during Roman times via the meandering Palaeo-Neckar depression, thus increasing both length and discharge of the Roman waterway. In this study, we present results of our investigations within the southern Hessische Ried to reconstruct the former channel network that was used by Romans for the transportation of troops, wares and border security. Our approach integrates the use of high-resolution digital elevation models (DEMs) as a base for geophysical measurements (electrical resistivity tomography, ERT), direct push sensing and sediment coring in combination with sedimentological and geochemical analyses of the encountered sedimentary units. Local chronostratigraphies were established based on radiocarbon dating. Based on our results, we are able to differentiate a palimpsest of several abandoned fluvial channels throughout the southern Hessische Ried and to reconstruct the spatio-temporal development of the corresponding fluvial systems. Chronostratigraphic data show that the Palaeo-Neckar stopped flowing through the Hessische Ried around 10 000 cal BCE. Moreover, we found that the river Weschnitz, the largest of the possible Landgraben tributaries, stopped flowing through the Palaeo-Neckar depression at ca. 3000 cal BCE. Instead, it took a right-angled shortcut westwards to the river Rhine, north of the city of Lorsch. For the first time, we present geomorphological evidence that the river Weschnitz was not diverted by the Romans as speculated so far. This is corroborated by numerous wooden posts of human-made construction crossing an E–W running water course at the modern Weschnitz knee, with the oldest posts being dendrochronologically dated to the fourth and third millennia BCE. We further argue that the river Winkelbach/Lauter formed its knee towards the river Rhine and thus left the Palaeo-Neckar depression not later than the second century CE but most probably even contemporaneously with the formation of the Weschnitz diversion. In the case of the Winkelbach/Lauter, a high-energy flood event presumably related to strong rainfall and/or meltwater processes in the Odenwald Mountains is assumed to be responsible for the initiation of the new, diverted water course. With regard to the Landgraben and its use as a waterway within the Roman fluvioscape of the Hessische Ried, we therefore conclude that the Romans successfully collected water from several smaller rivers, such as from the rivers Modau and Darmbach and from even smaller tributaries, to make the river Landgraben a navigable waterway. The rivers Weschnitz and Winkelbach/Lauter, however, did not contribute any water to the Landgraben system during Roman times.

Selective A3 adenosine receptor agonists have been shown to induce apoptosis in a variety of cell types. In this study we examined the effects of adenosine receptor agonists selective for A1, A2A, or A3 receptors on the induction of apoptosis in primary cultures of rat astrocytes and in C6 glial cells. Treatment of the cells with the A3 receptor agonist Cl-IB-MECA (10 microM) induced apoptosis in both cell types. The effects of Cl-IB-MECA were partially antagonized by the A3 receptor-selective antagonist MRS 1191. In contrast, the A1 and A2A receptor agonists, CPA and CGS 21680, respectively, did not have significant effects on apoptosis in these cells. Cl-IB-MECA reduced the expression of endogenous Bcl-2, whereas it did not affect the expression of Bax. Overexpression of Bcl-2 in C6 cells abrogated the induction of apoptosis induced by the A3 agonist. Cl-IB-MECA also induced an increase in caspase 3 activity and caspase inhibitors decreased the apoptosis induced by the A3 agonist. These findings suggest that intense activation of the A3 receptor is pro-apoptotic in glial cells via bcl2 and caspase-3 dependent pathways.

ImportanceUnderstanding the natural history of familial amyotrophic lateral sclerosis (ALS) caused by SOD1 mutations (ALSSOD1) will provide key information for optimising clinical trials in this patient population.ObjectiveTo establish an updated natural history of ALSSOD1.Design, setting and participantsRetrospective cohort study from 15 medical centres in North America evaluated records from 175 patients with ALS with genetically confirmed SOD1 mutations, cared for after the year 2000.Main outcomes and measuresAge of onset, survival, ALS Functional Rating Scale (ALS-FRS) scores and respiratory function were analysed. Patients with the A4V (Ala-Val) SOD1 mutation (SOD1A4V), the largest mutation population in North America with an aggressive disease progression, were distinguished from other SOD1 mutation patients (SOD1non-A4V) for analysis.ResultsMean age of disease onset was 49.7±12.3 years (mean±SD) for all SOD1 patients, with no statistical significance between SOD1A4V and SOD1non-A4V (p=0.72, Kruskal-Wallis). Total SOD1 patient median survival was 2.7 years. Mean disease duration for all SOD1 was 4.6±6.0 and 1.4±0.7 years for SOD1A4V. SOD1A4V survival probability (median survival 1.2 years) was significantly decreased compared with SOD1non-A4V (median survival 6.8 years; p<0.0001, log-rank). A statistically significant increase in ALS-FRS decline in SOD1A4V compared with SOD1non-A4V participants (p=0.02) was observed, as well as a statistically significant increase in ALS-forced vital capacity decline in SOD1A4V compared with SOD1non-A4V (p=0.02).Conclusions and relevanceSOD1A4V is an aggressive, but relatively homogeneous form of ALS. These SOD1-specific ALS natural history data will be important for the design and implementation of clinical trials in the ALSSOD1 patient population.

BackgroundAn important but often insufficient aspect of care in people with inflammatory arthritis (IA) is empowering patients to acquire a good understanding of their disease and building their ability to deal effectively with the practical, physical and psychological impacts of it. Self-management skills can be helpful in this regard.ObjectivesTo develop recommendations for the implementation of self-management strategies in IA.MethodsA multidisciplinary taskforce of 18 members from 11 European countries was convened. A systematic review and other supportive information (survey of healthcare professionals (HCPs) and patient organisations) were used to formulate the recommendations.ResultsThree overarching principles and nine recommendations were formulated. These focused on empowering patients to become active partners of the team and to take a more proactive role. The importance of patient education and key self-management interventions such as problem solving, goal setting and cognitive behavioural therapy were highlighted. Role of patient organisations and HCPs in promoting and signposting patients to available resources has been highlighted through the promotion of physical activity, lifestyle advice, support with mental health aspects and ability to remain at work. Digital healthcare is essential in supporting and optimising self-management and the HCPs need to be aware of available resources to signpost patients.ConclusionThese recommendations support the inclusion of self-management advice and resources in the routine management of people with IA and aim to empower and support patients and encourage a more holistic, patient-centred approach to care which could result in improved patient experience of care and outcomes.