Integrating single-cell multi-omics and prior biological knowledge for a functional characterization of the immune system.

The immune system comprises diverse specialized cell types that cooperate to defend the host against a wide range of pathogenic threats. Recent advancements in single-cell and spatial multi-omics technologies provide rich information about the molecular state of immune cells. Here, we review how the integration of single-cell and spatial multi-omics data with prior knowledge-gathered from decades of detailed biochemical studies-allows us to obtain functional insights, focusing on gene regulatory processes and cell-cell interactions. We present diverse applications in immunology and critically assess underlying assumptions and limitations. Finally, we offer a perspective on the ongoing technological and algorithmic developments that promise to get us closer to a systemic mechanistic understanding of the immune system.

Complementing Cell Taxonomies with a Multicellular Analysis of Tissues.

The application of single-cell molecular profiling coupled with spatial technologies has enabled charting of cellular heterogeneity in reference tissues and in disease. This new wave of molecular data has highlighted the expected diversity of single-cell dynamics upon shared external queues and spatial organizations. However, little is known about the relationship between single-cell heterogeneity and the emergence and maintenance of robust multicellular processes in developed tissues and its role in (patho)physiology. Here, we present emerging computational modeling strategies that use increasingly available large-scale cross-condition single-cell and spatial datasets to study multicellular organization in tissues and complement cell taxonomies. This perspective should enable us to better understand how cells within tissues collectively process information and adapt synchronized responses in disease contexts and to bridge the gap between structural changes and functions in tissues.

Discovery of new acetylcholinesterase inhibitors for Alzheimer's disease: virtual screening and in vitro characterisation.

For more than two decades, the development of potent acetylcholinesterase (AChE) inhibitors has been an ongoing task to treat dementia associated with Alzheimer's disease and improve the pharmacokinetic properties of existing drugs. In the present study, we used three docking-based virtual screening approaches to screen both ZINC15 and MolPort databases for synthetic analogs of physostigmine and donepezil, two highly potent AChE inhibitors. We characterised the in vitro inhibitory concentration of 11 compounds, ranging from 14 to 985 µM. The most potent of these compounds, S-I 26, showed a fivefold improved inhibitory concentration in comparison to rivastigmine. Moderate inhibitors carrying novel scaffolds were identified and could be improved for the development of new classes of AChE inhibitors.

Discrete-Point Analysis of the Energy Demand of Primary versus Secondary Metal Production.

The metal industry consumes large amounts of energy and contributes significantly, up to 10%, to global greenhouse gas (GHG) emissions. Recycling is commonly included among the most viable options for mitigating the climate forcing of metal production by replacing primary production. However, the recycling rates of metals are still incomplete and, in particular, do not exist for most specialty metals. Our empirical analysis of 48 metals shows that their recycling is mainly impeded by their low concentrations. In many cases, the metal concentration in end-of-life products is lower than that in natural ores. This phenomenon inevitably raises the question of the extent to which recycling can be conducted without losing its mitigating effects on climate change. We answer this question for two example metals, tantalum and copper, within the scope of Germany, a leader in recycling. For tantalum, the results show that a further increase in the end-of-life recycling rate (EOL-RR) could contribute to minimizing the overall energy consumption and GHG emissions, despite its low concentrations in end-of-life products. The energy requirements for recycling copper from end-of-life products already reach the magnitude of those for primary production. A further increase in EOL-RR must be examined in detail to ensure mitigating effects on climate change.

Iatrogenic Catheter-Induced Acute Aortic Dissection Type A after Coronary Angiography-A Retrospective Consecutive Case Series.

Background Acute aortic dissection type A (AADA) is one of the most life-threatening situations and surgical demanding procedures even today. Usually AADA develops spontaneously, but it can be related also to interventional procedures. Methods We analyzed the data of 14 patients surgically treated in our institution with catheter-induced AADA (ciAADA) during coronary angiography between January 2004 and December 2014. Data were compared with overall AADA patients in this time period (n = 288). Results Nine of the 14 patients were female. Subjects were significantly older compared to the AADA patients (69 ± 11 vs. 62 ± 11; p = 0.021). At admission, ciAADA patients were more often hemodynamically instable and mechanically ventilated. Twelve patients underwent replacement of the ascending aorta and two patients received a modified Bentall operation. Cardiopulmonary bypass time (210 ± 92 vs. 172 ± 51 min) and cross-clamp time (122 ± 63 vs. 92 ± 40 min) were significantly longer due to additional coronary artery bypass grafts in 71.4 versus 3.1% due to myocardial ischemia. Operative mortality (7.1 vs. 2.1%, p = 0.29) and 30-day mortality (50.0 vs. 10.7%, p < 0.001) were higher in the ciAADA group. Conclusion Coronary angiography-induced AADA is a rare but severe complication. Due to additional myocardial ischemia and preoperative hemodynamic instability, patients with ciAADA have adverse outcome compared to overall AADA patients.

The role of halide ions in the anisotropic growth of gold nanoparticles: a microscopic, atomistic perspective.

We provide a microscopic view of the role of halides in controlling the anisotropic growth of gold nanorods through a combined computational and experimental study. Atomistic molecular dynamics simulations unveil that Br(-) adsorption is not only responsible for surface passivation, but also acts as the driving force for CTAB micelle adsorption and stabilization on the gold surface in a facet-dependent way. The partial replacement of Br(-) by Cl(-) decreases the difference between facets and the surfactant density. Finally, in the CTAC solution, no halides or micellar structures protect the gold surface and further gold reduction should be uniformly possible. Experimentally observed nanoparticle's growth in different CTAB/CTAC mixtures is more uniform and faster as the amount of Cl(-) increases, confirming the picture from the simulations. In addition, the surfactant layer thickness measured on nanorods exposed to CTAB and CTAC quantitatively agrees with the simulation results.

Endovascular Aneurysm Sac Embolization for Treatment of Ruptured Aneurysms in the Aortoiliac Segment Using N-Butyl-Cyanoacrylate.

Background Aneurysmal rupture in the aortoiliac segment is a severe, life-threatening condition. Nowadays, in addition to surgical treatment, the implantation of a covered stent graft constitutes a feasible, minimally invasive treatment option. A novel approach is the add-on of transarterial aneurysm sac embolization with N-butyl-cyanoacrylate (NBCA). Here, we report our experience of performing this add-on embolization procedure after endovascular aneurysm repair for complex ruptured aneurysms of the aortoiliac segment. Material and Methods We describe six patients (mean age of 75.2 years; all male) with ruptured aneurysms in the visceral aortic and aortoiliac segment in whom a high-volume transarterial aneurysm sac embolization was performed as an add-on therapy to the implantation of an aortic prosthesis. The aim of this add-on intervention was to achieve the definite embolization of the aneurysmal rupture site and to ensure the best possible aneurysmal sealing. We report the feasibility, technical success, and considerations of using NBCA as well as clinical and follow-up imaging results, given their availability. Results Technical success was achieved in all cases. Clinical success was achieved in four cases. No periprocedural complications or reinterventions were reported. The mean full procedure time was 107.8 min. The mean radiation dose was 12,966.1 cGy/cm2. A mean amount of 10.7 mL of NBCA mixed with lipiodol in a 1:3 to 1:5 ratio was used for all patients. Available follow-up imaging up to 36 months after the procedure showed no aneurysm progression or endoleaks. In two patients, the NBCA cast had almost fully dissolved over the course of follow-up. Conclusions Our study underscores the notion that aneurysm sac embolization using high volumes of NBCA with ethiodized oil as an embolic agent is a feasible and add-on treatment option for optimizing the exclusion of the aneurysm from patients with ruptured aneurysms in the aortoiliac segment.

Functional bony entrapment of the dorsalis pedis artery caused by cranial subluxation in the talonavicular joint.

A 66-year-old female presented in the emergency department with Blue-Toe-Syndrome (BTS) and signs of osteitis of her left big toe. Imaging workup of the peripheral vasculature showed no findings. Upon invasive angiography, severe focal stenosis of the dorsalis pedis artery (DPA) could be seen at the talonavicular joint. Complete regression of the stenosis was inducible by dorsal extension in the ankle joint. Further imaging revealed an underlying subluxation of the talonavicular joint as cause of the arterial compression. Entrapment of the DPA is a rare condition and most often described in relation to connective tissue bands or variant muscular tendons (McCabe et al. 70:213-8, 2021; Weichman et al. 24:113, 2010; Smith et al.58:212-4, 2013; Griffin et al. 20:325-8; 2012). In the presented case, bony compression of the PDA due to cranial subluxation of the talus was seen as the cause of BTS and osteitis of the phalanx of the first toe.

Percutaneous creation of direct intrahepatic portosystemic shunts - an alternative for failed TIPS creation.

INTRODUCTION: Direct intrahepatic portosystemic shunt creation is a feasible and safe alternative for transjugular intrahepatic portosystemic shunt creation. It needs equipment like endovascular ultrasound with restricted availability. We performed the procedure percutaneously with a common interventional armamentarium to make it more feasible. METHODS: Retrospective analysis of 8 percutaneous DIPS insertions between 2016 and 2020. RESULTS: The procedure was successful in 8/8 patients. There was no short-term death reported within 30 days. The longest reported patency is 5 years. CONCLUSION: Percutaneous DIPS creation is a feasible alternative for failed TIPS. Percutaneously the procedure can be completed faster than conventional DIPS using only minimal puncture equipment. LEVEL OF EVIDENCE: Level 4, Case Series.

Experimental Evaluation of the Effectiveness of Aspiration-Based Techniques to Treat Different Types of Acute Thromboembolic Occlusions in the Femoropopliteal Vascular System Using an In Vitro Flow Model.

PURPOSE: In this in vitro study, the effectiveness and safety of four aspiration-based techniques for thrombectomy are evaluated for three types of thrombi in a flow model simulating the femoropopliteal segment. MATERIAL AND METHODS: Red, white, and mixed thrombi were produced in a standardized manner and used to simulate occlusion of a superficial femoral artery using a pulsatile flow model. Four techniques were compared: aspiration alone, aspiration + stent retriever, exposing thrombus to laser by an excimer laser system and a laser catheter + aspiration, and aspiration + mechanical fragmentation by a separator. Rate of first-pass recanalization, embolic events, and number of embolized fragments > 1 mm were compared. RESULTS: Aspiration alone, stent retriever, laser, and separator differed in rates of first-pass recanalization (53.3%; 86.6%; 20%; and 100%) and embolic events (40%; 93.3%; 73.3%; and 60%). Number of embolized fragments was lowest with aspiration and higher with separator, laser, and stent retriever. Rates of first-pass-recanalization (75%; 75%; and 45%) and embolic events (65%; 60%; and 75%) differed for red, white, and mixed thrombi. The mixed thrombus caused the highest number of embolized fragments, which was particularly high using the stent retriever. CONCLUSION: Additional use of mechanical techniques significantly enhances the effectiveness of thrombectomy but simultaneously provokes more embolism. Laser seems to negatively alter the structure of a thrombus and thus diminishes the effectiveness, while provoking embolism. All techniques had lowest effectiveness, but highest embolism with the mixed thrombus. This was particularly striking when a stent retriever was used with the mixed thrombus.

Percutaneous Thrombectomy in Patients with Occlusions of the Aortoiliac Segment: A Case Series.

OBJECTIVE: Thrombectomy of the aortoiliac segment remains a challenge for surgical and endovascular revision. This study aimed to evaluate the concept of percutaneous thrombectomy in patients with aortoiliac segment occlusions. MATERIALS & METHODS: Eighteen patients with aortoiliac occlusion who underwent percutaneous thrombectomy were retrospectively identified using the local picture archive and divided into the stent-graft (N = 10) and native vessels (N = 8) groups. The procedure was performed by placing a 12-24 French sheath adjacent to the distal end of the occluded vessel segment. The occlusion was passed with a balloon catheter which was retracted after inflation, to deliver the thrombus into the sheath. Technical success (reperfusion of the vessel and no residual thrombus/stenosis < 30%), complications and primary arterial patency were assessed. Follow-up included computed tomography angiography and evaluation of the clinical situation via telephone. RESULTS: Technical success was achieved in 38% (7/18) of patients after percutaneous thrombectomy alone and in 100% after additional procedures. The most common complication was peripheral embolism (44%, 8/18), which was treated successfully in all cases and was linked to a mismatch between the sheath and target vessel of ≥ 1 mm (P < .01). There were no significant differences in the incidence of complications between the two groups. Primary patency was 72% (13/18) with no significant difference between groups (P = .94). Follow-up CT scans were available for 13/18 patients (72%), with a mean follow-up time of 270 ± 146 days. All patients were contacted via phone (follow-up time, 653 ± 264 days). CONCLUSION: Percutaneous thrombectomy appears to be effective for revascularization of the aortoiliac segment, both in stent-grafts and in native vessels. The most common complication is peripheral embolism; however, the risk may be reduced by choosing an adequate sheath size.

Bispecific repurposed medicines targeting the viral and immunological arms of COVID-19.

Effective agents to treat coronavirus infection are urgently required, not only to treat COVID-19, but to prepare for future outbreaks. Repurposed anti-virals such as remdesivir and human anti-inflammatories such as barcitinib have received emergency approval but their overall benefits remain unclear. Vaccines are the most promising prospect for COVID-19, but will need to be redeveloped for any future coronavirus outbreak. Protecting against future outbreaks requires the identification of targets that are conserved between coronavirus strains and amenable to drug discovery. Two such targets are the main protease (Mpro) and the papain-like protease (PLpro) which are essential for the coronavirus replication cycle. We describe the discovery of two non-antiviral therapeutic agents, the caspase-1 inhibitor SDZ 224015 and Tarloxotinib that target Mpro and PLpro, respectively. These were identified through extensive experimental screens of the drug repurposing ReFRAME library of 12,000 therapeutic agents. The caspase-1 inhibitor SDZ 224015, was found to be a potent irreversible inhibitor of Mpro (IC50 30 nM) while Tarloxotinib, a clinical stage epidermal growth factor receptor inhibitor, is a sub micromolar inhibitor of PLpro (IC50 300 nM, Ki 200 nM) and is the first reported PLpro inhibitor with drug-like properties. SDZ 224015 and Tarloxotinib have both undergone safety evaluation in humans and hence are candidates for COVID-19 clinical evaluation.

Comparison of second-generation stents for application in the superficial femoral artery: an in vitro evaluation focusing on stent design.

PURPOSE: To examine and compare in an ex vivo study different nitinol stent designs intended for the superficial femoral artery (SFA) with regard to the appearance of fracture. METHODS: Seven different 8-×40-mm nitinol stents were evaluated (Misago, Absolute, Smart, Luminexx, Sentinol, Lifestent NT, and Sinus-Superflex). Finite element analysis (FEA) was used for digitalized stent design comparison; the strain during stent movement was calculated for bending, compression, and torsion. Additional mechanical fatigue tests for bending (70°), compression (40%), and torsion (twisted counterclockwise by 180°) were performed up to 650,000 cycles or until a fracture was observed. RESULTS: The FEA bending test showed that only the Misago, LifeStent, and Absolute stents presented no zones of high strain; in the torsion test, the Smart stent also had no zones of high strain. Macroscopic evaluation after mechanical bending indicated that the LifeStent performed the best (no stent fracture after 650,000 cycles). Misago and Absolute stents showed fractures at 536,000 cycles and 456,667 cycles, respectively (range 320,000-650,000 cycles). After compression and torsion testing, Misago showed no stent fracture after 650,000 cycles. The worst performing stent was Luminexx during all test cycles. CONCLUSION: The 7 SFA stents showed differences in the incidence of high strain zones, which indicates a potential for stent fracture, as demonstrated by the mechanical fatigue tests. Differences in stent design might play a major role in the appearance of stent strut fracture related to restenosis and reocclusion.

Embolic protection devices for peripheral application: wasteful or useful?

Distal embolization following percutaneous intervention is a universal phenomenon that has been reported in various vascular beds. Distal emboli are also very common during lower extremity percutaneous peripheral interventions. Some data from case reports and registries are currently available. Clinical data have shown that the application of an embolic protection device in the lower limb arteries is safe. Prospective and, ideally, randomized trial data are warranted to justify the increased use of filters in lower extremity interventions, despite the obvious benefits that these devices provide. However, the clinical relevance of distal embolization in the lower extremity remains unquantified.

Highly Enantioselective Hiyama Cross-Coupling via Rh-Catalyzed Allylic Arylation of Racemic Allyl Chlorides.

Highly enantioselective Hiyama cross-coupling reactions have been achieved through rhodium(I)-catalyzed dynamic kinetic asymmetric transformations between aryl siloxanes and cyclic racemic allyl halides. This process affords valuable enantiomerically enriched aryl-substituted cyclic allyl products and is compatible with heterocyclic allyl chloride electrophiles.

Author Correction: Asymmetric Suzuki-Miyaura coupling of heterocycles via Rhodium-catalysed allylic arylation of racemates.

This corrects the article DOI: 10.1038/ncomms15762.

Renovascular hypertension: endovascular therapy in complicated aortic Stanford type B dissection.

A 63 years old male with a history of arterial hypertension presented with a current onset of chest pain and discrete headaches accompanied with dizziness. His blood pressure, 210/110 mmHg, had worsened and showed a reversed circadian rhythm with an average of 150/90 mmHg during night time. A CT angiography of the aorta demonstrated a type B dissection involving the right renal artery causing reduced perfusion of the right kidney. Subsequent invasive aortic angiography showed a continuously moving aortic dissection flap resulting in a dynamic stenosis proven by varying pressure gradients of between 5 and 35 mmHg. Stent placement of the renal artery ostium kept the vessel open and fixed the reno-aortic dissection flap in order to prevent it from progressing into the right kidney. Follow-up examinations revealed improved blood pressure control allowing for physiologic drop of blood pressure during night-time.

[Endovascular treatment of atherosclerotic arterial stenoses and occlusions of the supraaortic arteries: mid-term results from a single center analysis]. / Endovaskuläre Behandlung arteriosklerotisch bedingter arterieller Stenosen und Okklusionen der Aortenbogengefässe: Mittelfristige Ergebnisse einer Ein-center-Analyse.

OBJECTIVE: To determine mid-term patency rates after endovascular treatment of supraaortic atherosclerotic arterial stenoses and occlusions using percutaneous transluminal angioplasty (PTA) and stent placement. PATIENTS AND METHODS: During a period of 83 months, 48 patients (18 female, 30 male; mean age 61 years, range 31-82 years) were included into this prospective single-center study. Fifty-five lesions of the brachial and cephalic arteries (subclavian/axillary artery n = 42, innominate artery n = 7, origin common carotid artery n = 6) were treated using PTA (n = 38), PTA plus stent (n = 11) or primary stent placement (n = 6). For anticoagulation, patients received a bolus of heparin (5000 IU) intraarterially during the intervention followed by intravenous application for 24h. At discharge, life-time application of ASA (100mg/day) was initiated. Follow-up protocol included clinical examination, colour-coded duplex ultrasound and intraarterial angiography in case of re-stenosis. RESULTS: PTA and stent placement were technically successful in all patients (100%). No major complications occurred. Of seven patients presenting with total occlusions, six were treated with stent placement. Stent implantation was also performed in all lesions located at the origin of the supraaortic arteries (n = 6). In 38 lesions, the result of PTA was satisfactory. Mean follow-up time is 22 months (range 1-83 months). During follow-up examinations, re-stenoses occurred in 10 cases (at 1 month n = 2, at 6 months n = 2, at 12 months n = 3, at 24 months n = 3). In 9 lesions, re-interventions were performed (PTA n = 7; PTA plus stent n = 2). According to Kaplan-Meier life-table analysis, cumulative primary and primary assisted patency rates are 69.5% (patients at risk n = 15; standard error 9%) and 90.6% (patients at risk n = 16; standard error 6.3%) at 20 months, respectively. CONCLUSIONS: Endovascular treatment of atherosclerotic obstructive disease in brachial and cephalic arteries is a safe procedure showing promising mid-term patency rates.

Asymmetric cross-coupling of alkyl, alkenyl and (hetero)aryl nucleophiles with racemic allyl halides.

Single enantiomer molecules are important for the pharmaceutical and agrochemical industries and increasingly so in materials science. Most strategies to obtain enantiomerically enriched molecules rely on either generating new stereogenic centres from prochiral substrates or resolving racemic mixtures of enantiomers. Dynamic asymmetric processes are powerful methods that use racemic mixtures of chiral substrates as starting material. This Feature Article focuses on asymmetric additions to racemic substrates using non-stabilized sp2- and sp3-hybridized nucleophiles. These reactions bear considerable resemblance to traditional sp2-sp2 cross-coupling reactions in terms of the starting materials used and the products obtained, but the reaction mechanisms are necessarily different.

Asymmetric Suzuki-Miyaura coupling of heterocycles via Rhodium-catalysed allylic arylation of racemates.

Using asymmetric catalysis to simultaneously form carbon-carbon bonds and generate single isomer products is strategically important. Suzuki-Miyaura cross-coupling is widely used in the academic and industrial sectors to synthesize drugs, agrochemicals and biologically active and advanced materials. However, widely applicable enantioselective Suzuki-Miyaura variations to provide 3D molecules remain elusive. Here we report a rhodium-catalysed asymmetric Suzuki-Miyaura reaction with important partners including aryls, vinyls, heteroaromatics and heterocycles. The method can be used to couple two heterocyclic species so the highly enantioenriched products have a wide array of cores. We show that pyridine boronic acids are unsuitable, but they can be halogen-modified at the 2-position to undergo reaction, and this halogen can then be removed or used to facilitate further reactions. The method is used to synthesize isoanabasine, preclamol, and niraparib-an anticancer agent in several clinical trials. We anticipate this method will be a useful tool in drug synthesis and discovery.