We describe MUSCLE, a new computer program for creating multiple alignments of protein sequences. Elements of the algorithm include fast distance estimation using kmer counting, progressive alignment using a new profile function we call the logexpectation score, and refinement using treedependent restricted partitioning. The speed and accuracy of MUSCLE are compared with T-Coffee, MAFFT and CLUSTALW on four test sets of reference alignments: BAliBASE, SABmark, SMART and a new benchmark, PREFAB. MUSCLE achieves the highest, or joint highest, rank in accuracy on each of these sets. Without refinement, MUSCLE achieves average accuracy statistically indistinguishable from T-Coffee and MAFFT, and is the fastest of the tested methods for large numbers of sequences, aligning 5000 sequences of average length 350 in 7 min on a current desktop computer. The MUSCLE program, source code and PREFAB test data are freely available at http://www.drive5. com/muscle.

MUSCLE: multiple sequence alignment with high accuracy and high throughput

CHARMM (Chemistry at HARvard Macromolecular Mechanics) is a highly flexible computer program which uses empirical energy functions to model macromolecular systems. The program can read or model build structures, energy minimize them by first- or second-derivative techniques, perform a normal mode or molecular dynamics simulation, and analyze the structural, equilibrium, and dynamic properties determined in these calculations. The operations that CHARMM can perform are described, and some implementation details are given. A set of parameters for the empirical energy function and a sample run are included.

CHARMM: A program for macromolecular energy, minimization, and dynamics calculations

For a successful analysis of the relation between amino acid sequence and protein structure, an unambiguous and physically meaningful definition of secondary structure is essential. We have developed a set of simple and physically motivated criteria for secondary structure, programmed as a pattern-recognition process of hydrogen-bonded and geometrical features extracted from x-ray coordinates. Cooperative secondary structure is recognized as repeats of the elementary hydrogen-bonding patterns “turn” and “bridge.” Repeating turns are “helices,” repeating bridges are “ladders,” connected ladders are “sheets.” Geometric structure is defined in terms of the concepts torsion and curvature of differential geometry. Local chain “chirality” is the torsional handedness of four consecutive Cα positions and is positive for right-handed helices and negative for ideal twisted β-sheets. Curved pieces are defined as “bends.” Solvent “exposure” is given as the number of water molecules in possible contact with a residue. The end result is a compilation of the primary structure, including SS bonds, secondary structure, and solvent exposure of 62 different globular proteins. The presentation is in linear form: strip graphs for an overall view and strip tables for the details of each of 10.925 residues. The dictionary is also available in computer-readable form for protein structure prediction work.

Dictionary of protein secondary structure: pattern recognition of hydrogen-bonded and geometrical features

6.2.2. Definition of Effective Properties 3064 6.3. Response Properties to Magnetic Fields 3066 6.3.1. Nuclear Shielding 3066 6.3.2. Indirect Spin−Spin Coupling 3067 6.3.3. EPR Parameters 3068 6.4. Properties of Chiral Systems 3069 6.4.1. Electronic Circular Dichroism (ECD) 3069 6.4.2. Optical Rotation (OR) 3069 6.4.3. VCD and VROA 3070 7. Continuum and Discrete Models 3071 7.1. Continuum Methods within MD and MC Simulations 3072

/pdf/quantum-mechanical-continuum-solvation-models-3edv963g14.pdf

Quantum mechanical continuum solvation models.

This article describes the software suite GROMACS (Groningen MAchine for Chemical Simulation) that was developed at the University of Groningen, The Netherlands, in the early 1990s. The software, written in ANSI C, originates from a parallel hardware project, and is well suited for parallelization on processor clusters. By careful optimization of neighbor searching and of inner loop performance, GROMACS is a very fast program for molecular dynamics simulation. It does not have a force field of its own, but is compatible with GROMOS, OPLS, AMBER, and ENCAD force fields. In addition, it can handle polarizable shell models and flexible constraints. The program is versatile, as force routines can be added by the user, tabulated functions can be specified, and analyses can be easily customized. Nonequilibrium dynamics and free energy determinations are incorporated. Interfaces with popular quantum-chemical packages (MOPAC, GAMES-UK, GAUSSIAN) are provided to perform mixed MM/QM simulations. The package includes about 100 utility and analysis programs. GROMACS is in the public domain and distributed (with source code and documentation) under the GNU General Public License. It is maintained by a group of developers from the Universities of Groningen, Uppsala, and Stockholm, and the Max Planck Institute for Polymer Research in Mainz. Its Web site is http://www.gromacs.org.

/pdf/gromacs-fast-flexible-and-free-15aazpel5u.pdf

GROMACS: Fast, flexible, and free

OBJECTIVE
Flow diverters have revolutionized the endovascular treatment of intracranial aneurysms. Here, the authors present the first large-scale North American multicenter experience using the Flow Redirection Endoluminal Device (FRED) in the treatment of cerebral aneurysms.


METHODS
Consecutive cerebral aneurysms treated with FRED at 7 North American centers between June 2020 and November 2021 were included. Data collected included patient demographic characteristics, aneurysm characteristics, periprocedural and long-term complications, modified Rankin Scale (mRS) scores, and radiological follow-up.


RESULTS
In total, 133 aneurysms in 116 patients were treated with 123 FRED deployment procedures and included in this study. One hundred twenty-six aneurysms (94.7%) were unruptured, 117 (88.0%) saccular, and 123 (92.5%) located in anterior circulation. The mean (range) aneurysm maximal width and neck width sizes were 7.2 (1.5-42.5) mm and 4.1 (1.0-15.1) mm, respectively. Successful FRED deployment was achieved in 122 procedures (99.2%). Adjunctive coiling was used in 4 procedures (3.3%). Radiological follow-up was available for 101 aneurysms at a median duration of 7.0 months. At last follow-up, complete occlusion was observed in 55.4% of patients, residual neck in 8.9%, and filling aneurysm in 35.6%; among cases with radiological follow-up duration > 10 months, these values were 21/43 (48.8%), 3/43 (7.0%), and 19/43 (44.2%), respectively. On multivariate regression analysis, age (OR 0.93, p = 0.001) and aneurysm neck size (OR 0.83, p = 0.048) were negatively correlated with odds of complete occlusion at latest follow-up. The retreatment rate was 6/124 (4.8%). The overall complication rate was 31/116 (26.7%). Parent vessel occlusion, covered branch occlusion, and in-stent stenosis were detected in 9/99 (9.1%), 6/63 (9.5%), and 15/99 (15.2%) cases, respectively. The FRED-related, symptomatic, thromboembolic, and hemorrhagic complication rates were 22.4%, 12.9%, 6.9%, and 0.9% respectively. The morbidity rate was 10/116 patients (8.6%). There was 1 death due to massive periprocedural internal carotid artery stroke, and 3.6% of the patients had an mRS score > 2 at the last follow-up (vs 0.9% at baseline).


CONCLUSIONS
As the first large-scale North American multicenter FRED experience, this study confirmed the ease of successful FRED deployment but suggested lower efficacy and a higher rate of complications than reported by previous European and South American studies on FRED and other flow-diverting devices. The authors recommend judicious use of this device until future studies can better elucidate the long-term outcomes of FRED treatment.

North American multicenter experience with the Flow Redirection Endoluminal Device in the treatment of intracranial aneurysms.

A 64-year-old Caucasian woman presented with abdominal pain associated with weight gain, lethargy and night sweats. Abdominal examination revealed a large lower abdominal mass. A colonoscopy was performed which showed no mucosal abnormalities. However, CT (Fig. 1) and MRI (Fig. 2) scans showed an encapsulated fatty pelvic tumour with two central enhancing nodules confined in the sigmoid mesocolon and upper mesorectum with no local invasion of surrounding structures and no evidence of nodal or distant metastases. A diagnosis of liposarcoma confined in the sigmoid and rectal mesentery was suggested. This case was discussed at the St John of God Subiaco Hospital weekly colorectal multidisciplinary team meeting and surgery was considered to be the optimal initial treatment. At operation, the mass was confined to the sigmoid mesocolon and the upper twothirds of the mesorectum displacing but not invading adjacent loops of intestine. Complete macroscopic resection of the mass was achieved by undertaking a standard ‘ultra-low’ anterior resection for a primary rectal adenocarcinoma employing total mesorectal excision, high ligation of the inferior mesenteric vessels and restoration of intestinal continuity using a colonic pouch and diverting loop ileostomy. The surgical specimen was a 580-mm long anterior resection with attached mesocolon and mesorectum, within which there was a lobulated fatty mass measuring 270 × 230 × 70 mm. Histologic examination of the specimen confirmed the presence of a welldifferentiated liposarcoma (WDLPS) (Fig. 3). At the nonperitonealized deep surface of the specimen, there was tumour extension but the presence of normal mature fat suggested that the excision was likely complete. Adjuvant chemotherapy was not considered to be required. Postoperative recovery was smooth and the ileostomy has subsequently been closed with the establishment of satisfactory early bowel function. Liposarcoma, a malignant mesenchymal neoplasm of lipogenic tissue, is most commonly found in the extremities and retroperitoneum. It is one of the most common histotype of soft tissue sarcomas and can be further subdivided into four subtypes: (i) WDLPS/atypical lipomatous tumour (ALT); (ii) dedifferentiated liposarcoma; (iii) myxoid liposarcoma/round-cell liposarcoma; and

The colorectal surgeon's liposarcoma

INTRODUCTION: The pathogenesis of intracranial aneurysms (IAs) is complex, with both genetic and environmental risk factors. Much effort has been devoted to identifying the molecular mechanisms of IAs to develop new therapies halting the progression of IAs. METHODS: Deep whole exome sequencing was performed for 11 anterior circulation, sporadic saccular IAs from 10 unrelated patients. Paired aneurysm-peripheral blood DNA samples were compared to evaluate the somatic saccular aneurysm exome alterations. Variants were validated with deep next generation sequencing methods. The genetic landscape of a validation cohort of 60 aneurysms was analyzed by targeted deep sequencing of a vascular panel of genes. RESULTS: Whole exome sequencing revealed somatic variants in 7 of 11 saccular aneurysms. Most coding somatic variants found were missense (68%). Somatic variants in multiple genes were common, all falling into similar allele frequencies (3-18%). Two aneurysms from one patient underwent exome sequencing with differing alterations (Acom with no alterations and MCA with 20 variants with about 8% allele frequencies). Targeted sequencing validation of these in a larger cohort revealed alterations in similar allele fractions. Saccular aneurysms harbored variants in genes falling into several functional categories including angiogenesis (PKD1), DNA repair (SFB3, DCC, MLH1), ECM (COL4A5, MMP8) and cancer genes (ERBb4 and PTCH1). Double variants, predicted to be protein/function altering were found in the following genes: DCC, ATXN1L, CCDC178, GAD2, IARS2, ERBb4, COL4A5, FAM122C, ANK2, SF3B3, ADCY7, ABCB4 and RAB11FIP1. CONCLUSION: Anterior circulation saccular IAs harbor somatic low allele fraction variants in coding genes predicted to alter protein function. Allele fractions occurred in a similar range within and between samples suggesting a cell-based population driving the pathogenesis of saccular IAs. Recurrent variants in genes known to be involved in IAs (PKD1 and COL4A5) and novel genes (ERBb4 and FAM122C) are new frontiers for further research.

416 Low Allele Frequency Somatic Variants in Sporadic Saccular “Berry” Cerebral Aneurysms

Geburt und Zukunft der Multiskalenmodellierung von makromolekularen Systemen (Nobel‐Aufsatz)

Renal infarction is a rare entity that presents similarly to other common renal conditions such as nephrolithiasis, which can often result in a missed or delayed diagnosis. As a result, a high degree of suspicion for this diagnosis is warranted in patients presenting with flank pain. We present a patient with recurrent nephrolithiasis who presented with flank pain. A subsequent workup revealed a renal infarct due to underlying renal artery thrombosis. We also explore if there was a possible mechanism between this event and his history of recurrent nephrolithiasis.

/pdf/renal-artery-thrombosis-leading-to-renal-infarct-in-a-1qfrnq54.pdf

Michael Levitt

Papers

North American multicenter experience with the Flow Redirection Endoluminal Device in the treatment of intracranial aneurysms.

The colorectal surgeon's liposarcoma

416 Low Allele Frequency Somatic Variants in Sporadic Saccular “Berry” Cerebral Aneurysms

Geburt und Zukunft der Multiskalenmodellierung von makromolekularen Systemen (Nobel‐Aufsatz)

Renal Artery Thrombosis Leading to Renal Infarct in a Patient With Recurrent Nephrolithiasis