Exploration of isatin-based inhibitors of SARS-CoV-2 Nsp15 endoribonuclease.

The global health crisis caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) urges the development of new antiviral agents with broad coronavirus coverage. Due to its key role in viral evasion from the host innate immune response, the coronavirus Nsp15 uridine-specific endoribonuclease (EndoU) is of high interest as a drug target. Considering that the isatin scaffold is well-known for its versatile pharmacological properties, we synthesized and evaluated a series of compounds carrying an isatin core.

A Versatile Class of 1,4,4-Trisubstituted Piperidines Block Coronavirus Replication In Vitro.

There is a clear need for novel antiviral concepts to control SARS-CoV-2 infection. Based on the promising anti-coronavirus activity observed for a class of 1,4,4-trisubstituted piperidines, we here conducted a detailed analysis of the structure-activity relationship of these structurally unique inhibitors. Despite the presence of five points of diversity, the synthesis of an extensive series of analogues was readily achieved by Ugi four-component reaction from commercially available reagents.

Impact of SARS-CoV-2 Spike Mutations on Its Activation by TMPRSS2 and the Alternative TMPRSS13 Protease.

The continuous emergence of new variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) urges better understanding of the functional motifs in the spike (S) protein and their tolerance to mutations. Here, we focused on the S2' motif, which, during virus entry, requires cleavage by a host cell protease to release the fusion peptide. Though belonging to an immunogenic region, the SARS-CoV-2 S2' motif (811-KPSKR-815) has shown hardly any variation, with its three basic (K/R) residues being >99.

The SARS-CoV-2 and other human coronavirus spike proteins are fine-tuned towards temperature and proteases of the human airways.

The high transmissibility of SARS-CoV-2 is related to abundant replication in the upper airways, which is not observed for the other highly pathogenic coronaviruses SARS-CoV and MERS-CoV. We here reveal features of the coronavirus spike (S) protein, which optimize the virus towards the human respiratory tract. First, the S proteins exhibit an intrinsic temperature preference, corresponding with the temperature of the upper or lower airways.

Betulonic Acid Derivatives Interfering with Human Coronavirus 229E Replication via the nsp15 Endoribonuclease.

To develop antiviral therapeutics against human coronavirus (HCoV) infections, suitable coronavirus drug targets and corresponding lead molecules must be urgently identified. Here, we describe the discovery of a class of HCoV inhibitors acting on nsp15, a hexameric protein component of the viral replication-transcription complexes, endowed with immune evasion-associated endoribonuclease activity. Structure-activity relationship exploration of these 1,2,3-triazolo-fused betulonic acid derivatives yielded lead molecule as a strong inhibitor (antiviral EC: 0.

The error-related negativity for error processing in interoception.

The error-related negativity (ERN) is an event-related potential in the electroencephalogram (EEG) observed within the first 100 ms after commission of an error. Increased ERN amplitudes have been observed in several psychological disorders characterized by high negative affect. While the ERN has extensively been studied in tasks using exteroceptive stimuli, its relation to interoceptive stimuli is unknown.

Considerations on anthropometric measurements of the female breast.

Anthropometric measurements of the breasts and their relevant position taken from fixed skeletal points provide a useful tool in the accurate evaluation of patients preoperatively and the assessment of surgical results. This paper presents the clinical correlation obtained by statistical analysis of the results of measurements of 973 women.

Implementation of parameters in the expansion ratio of mesh skin grafts.

Expansion of a mesh skin graft depends on factors pertaining to the graft itself as well as on parameters of the meshing device. With regard to the graft, we examine the efficiency of graft handling and thickness of the skin graft. With regard to the parameters of the meshing apparatus, which determine the expansion ratio: (1) d equals the distance between the cutting blades, which will become the width of the mesh ribbons and is an underestimated parameter for expansion; and (2) L equals the length of cut, which determines proportionally the expansion ratio.

Lymphangiectomy and treatment modalities in Merkel cell carcinoma: a report of five new cases.

Merkel-cell trabecular carcinoma of the skin has a prognosis poorer than expected for a small skin lesion. Surgery is central to actual treatment. A wide excision is indicated for localized disease.

A review of skin meshers.

Before the widespread clinical acceptance of mesh skin grafting, expansion of full thickness skin had already been reported. The senior authors, who performed the first mesh skingrafts, have tried several variations of instruments starting with a flat block, later using a roller device with staggered cuts (Mesh Dermatome type I), and further a roller with continuous cuts and a grooved carrier (Mesh Dermatome II). Now interchangeable rollers for different expansions (Zimmer Skin Mesher) and several other genuine meshers are available.

Photoelectric plethysmography in monitoring skin circulation.

Photoelectric plethysmography is not new, but is a simple noninvasive technique to determine erythrocyte volume and oxygen saturation. The data are immediately available, accurate, repeatable, and recordable. Methods currently used for estimating microcirculation and oxygen saturation include clinical tests such as observation of skin color, temperature changes, capillary refill, and bleeding; chemical tests such as fluorscein injection; radioactive isotopes (24Na, 131I, 99mTc, and 133Xe); and instrumental methods (both invasive and noninvasive) such as temperature and infrared thermometry, thermocouples, oxygen probes, and/or the plethysmometer.

Action of neurotropin on cold-induced pain in normal volunteers: a double-blind placebo study.

The analgesic action of neurotropin, a biological compound widely used in Japan with a record of very limited side-effects, was tested in 8 Caucasian normal volunteers. For the pain test, the subjects were requested to immerse the right hand in ice-cold water and to report the appearance of the following sensations: pain threshold (PThr) and tolerance to pain (PTol). Pain sensitivity range (PSR) was calculated by difference between PThr and PTol expressed in s from beginning of immersion.

[Use of absorbable suture material for the correction of prominent ears (author's transl)].

The ester of the polyglycolic acid is very useful to maintain a correction of prominent ears. The good tolerance and longstanding traction force allow a satisfactory healing of the cartilage. Catgut for skin closure behind the ear has the psychological advantage of not having to be removed.

Hair transplantation using local hypothermia.

The frequency of hair transplantation for treatment of male alopecia is increasing, and much time is consumed in free scalp plug removal and implantation. The amount of time depends upon the number of grafts required. Plugs ranging in diameter from 2 to 4 mm are recommended since larger sizes have increased fibrosis and decreased hair growth.

Correction of extensive neck contractures with local flaps and split- and full-thickness grafts.

A technic of combined split-thickness and full-thickness skin grafts and local flap closure for extensive deep cicatricial neck contractures is presented. The head and neck are mobilized by excision of limiting tissues. The lateral neck skin is mobilized to be rotated anteriorly as flaps, and a full-thickness skin graft is applied to the central neck.

[Reappraisal of the problem of hair transplantation (author's transl)].

Free transplants of hair-bearing scalp as "plugs" or "strips" are an adequate treatment for male alopecia. Cooling the grafts eliminates hematoma and infection and allows successful take and growth of larger plugs. However the result of grafting wide hairstrips is unreliable.