cometadata/datacite-titles-descriptions-related-identifiers huggingface dataset:
DOI: 10.5281/zenodo.10561418
title: Supplementary data for: The mechanism of mammalian proton-coupled peptide transporters

description: This is the supplementary data for our paper "The mechanism of mammalian proton-coupled peptide transporters".

Abstract:

Proton-coupled oligopeptide transporters (POTs) are of great pharmaceutical interest owing to their promiscuoussubstrate binding site that has been linked to improved oral bioavailability of several classes of drugs. Members of thePOT family are conserved across all phylogenetic kingdoms and function by coupling peptide uptake to the protonelectrochemical gradient. Cryo-EM structures and alphafold models have recently provided new insights into differentconformational states of two mammalian POTs, SLC15A1 and SLC15A2. Nevertheless, these studies leave openimportant questions regarding the mechanism of proton and substrate coupling, while simultaneously providing aunique opportunity to investigate these processes using molecular dynamics (MD) simulations. Here, we employextensive unbiased and enhanced-sampling MD to map out the full SLC15A2 conformational cycle and itsthermodynamic driving forces. By computing conformational free energy landscapes in different protonation states andin the absence or presence of peptide substrate, we identify a likely sequence of intermediate protonation steps thatdrive inward-directed alternating access. These simulations identify key differences in the extracellular gate betweenmammalian and bacterial POTs, which we validate experimentally in cell-based transport assays. Our results fromconstant-PH MD and absolute binding free energy (ABFE) calculations also establish a mechanistic link between protonbinding and peptide recognition, revealing key details underpining secondary active transport in POTs. This studyprovides a vital step forward in understanding proton-coupled peptide and drug transport in mammals and pave theway to integrate knowledge of solute carrier structural biology with enhanced drug design to target tissue and organbioavailability.

 

This project was funded by the Wellcome Trust (Grant ID: 218514/Z/19/Z). Compute resources were also provided bythe EPSRC ARCHER2, Jade 2 and N8 CIR BEDE facilities, granted via the High-End Computing Consortium for BiomolecularSimulation (HECBioSim), supported by EPSRC (EP/X035603/1).
DOI: 10.6084/m9.figshare.24924057
title: Supplementary Material for: Gastric Lipomas: A Case Series and Review of the Literature

description: Typically found incidentally, the purpose of this case series was to review the presentation of a rare subset of tumors known as gastric lipomas after identifying two cases within our institution within a short period of time. With the advent of new radiologic investigations such as Computed Tomography and Magnetic resonance imaging and advances in endoscopy there are new approaches to identifying and managing these tumors. On further evaluation of the literature, we found that despite the availability of minimally invasive endoscopic techniques such as mucosal resection and submucosal dissection in the setting of large tumors most patients tend to have to resort to surgical management. Further research into the management of these tumors endoscopically is needed. There is also evidence to suggest that an association with malignancy due to long term inflammation of overlying mucosa should be explored fur
DOI: 10.6084/m9.figshare.24924057.v1
title: Supplementary Material for: Gastric Lipomas: A Case Series and Review of the Literature

description: Typically found incidentally, the purpose of this case series was to review the presentation of a rare subset of tumors known as gastric lipomas after identifying two cases within our institution within a short period of time. With the advent of new radiologic investigations such as Computed Tomography and Magnetic resonance imaging and advances in endoscopy there are new approaches to identifying and managing these tumors. On further evaluation of the literature, we found that despite the availability of minimally invasive endoscopic techniques such as mucosal resection and submucosal dissection in the setting of large tumors most patients tend to have to resort to surgical management. Further research into the management of these tumors endoscopically is needed. There is also evidence to suggest that an association with malignancy due to long term inflammation of overlying mucosa should be explored fur
DOI: 10.6084/m9.figshare.24912522.v1
title: Supplementary Material for: Internal carotid artery dissection presenting with transient or subclinical Horner syndrome

description: Introduction

The most frequently encountered symptoms in internal carotid artery dissection (ICAD) are head or neck pain and cerebral ischemia. Ocular symptoms or signs have been reported as the presenting feature in up to 50% of patients, with (painful) Horner syndrome being the most frequently associated. Horner syndrome is part of the classic triad that depicts the characteristic presentation of ICAD, and that consists of pain in the ipsilateral neck, head and orbital regions, (partial) Horner syndrome, and cerebral or retinal ischemia. All patients presenting with painful Horner syndrome should therefore require prompt investigations to rule out carotid artery dissection. In patients with confirmed diagnosis, treatment should be started early to prevent permanent ocular or cerebral complications.

Case Presentation

Case 1: A 61-year-old woman presented with right temporal headache, an episode of transient visual loss and drooping of the right upper eyelid. Examination revealed anisocoria, which was more important in darkness. Reversal of anisocoria was observed after instilling drops of apraclonidine 0.5%. Neuro-imaging demonstrated intrapetrous ICAD. Headaches, eyelid ptosis and anisocoria all had resolved the next day. Apraclonidine pharmacologic testing a few weeks later was no longer dilating the smaller pupil. 

Case 2: A 48-year-old man presented with drooping of the right upper eyelid and right occipital headache and facial pain that all started one day after an intense yoga workout. Anisocoria was noticed upon examination, with topical cocaine 10% pharmacologic testing confirming a right Horner syndrome. Neuro-imaging revealed ICAD. The patient reported resolution of his eyelid ptosis a few days later. Eyelid ptosis and anisocoria had indeed resolved at a follow-up examination a few weeks later. However, cocaine drop testing still produced anisocoria, compatible with subclinical Horner syndrome. 

Conclusion

Transient or subclinical Horner syndrome can be the presenting feature in ICAD; in such cases, the characteristic eyelid ptosis and anisocoria may be short-lived and resolve in only a few days. If suspected by clinical history, pharmacologic testing may be helpful in identifying subclinical cases.
DOI: 10.6084/m9.figshare.24912522
title: Supplementary Material for: Internal carotid artery dissection presenting with transient or subclinical Horner syndrome

description: Introduction

The most frequently encountered symptoms in internal carotid artery dissection (ICAD) are head or neck pain and cerebral ischemia. Ocular symptoms or signs have been reported as the presenting feature in up to 50% of patients, with (painful) Horner syndrome being the most frequently associated. Horner syndrome is part of the classic triad that depicts the characteristic presentation of ICAD, and that consists of pain in the ipsilateral neck, head and orbital regions, (partial) Horner syndrome, and cerebral or retinal ischemia. All patients presenting with painful Horner syndrome should therefore require prompt investigations to rule out carotid artery dissection. In patients with confirmed diagnosis, treatment should be started early to prevent permanent ocular or cerebral complications.

Case Presentation

Case 1: A 61-year-old woman presented with right temporal headache, an episode of transient visual loss and drooping of the right upper eyelid. Examination revealed anisocoria, which was more important in darkness. Reversal of anisocoria was observed after instilling drops of apraclonidine 0.5%. Neuro-imaging demonstrated intrapetrous ICAD. Headaches, eyelid ptosis and anisocoria all had resolved the next day. Apraclonidine pharmacologic testing a few weeks later was no longer dilating the smaller pupil. 

Case 2: A 48-year-old man presented with drooping of the right upper eyelid and right occipital headache and facial pain that all started one day after an intense yoga workout. Anisocoria was noticed upon examination, with topical cocaine 10% pharmacologic testing confirming a right Horner syndrome. Neuro-imaging revealed ICAD. The patient reported resolution of his eyelid ptosis a few days later. Eyelid ptosis and anisocoria had indeed resolved at a follow-up examination a few weeks later. However, cocaine drop testing still produced anisocoria, compatible with subclinical Horner syndrome. 

Conclusion

Transient or subclinical Horner syndrome can be the presenting feature in ICAD; in such cases, the characteristic eyelid ptosis and anisocoria may be short-lived and resolve in only a few days. If suspected by clinical history, pharmacologic testing may be helpful in identifying subclinical cases.
DOI: 10.6084/m9.figshare.24885303
title: Supplementary Material for: Two Japanese Families with Pigmented Paravenous Retinochoroidal Atrophy and the HK1 Mutation: a Case Report

description: Hexokinase 1 (HK1) gene is the cause of autosomal dominant retinitis pigmentosa (RP) 79. To date, only the E874K mutation has been reported as the causative mutation in patients with non-syndromic RP. As a Caucasian RP case with a pathological variant of HK1 exhibiting pigmented paravenous retinochoroidal atrophy (PPRCA) phenotype was recently reported, we reviewed RP79 cases in our Japanese RP cohort. Consequently, two Japanese patients, who were diagnosed with RP79 by genetic tests in our RP cohort, were included in this study. Patient 1 was a 60-year-old woman. Fundus examination revealed symmetrical donut-shaped retinal degeneration, with pigment deposition avoiding the macula. Moreover, degeneration extended in a peripheral direction along the vessels like a starfish, and degeneration was observed around the veins and arteries. Patient 2 was a 75-year-old man. Fundus examination revealed symmetric macula-avoiding donut-shaped retinal degeneration, with paravenous protruding degeneration along the blood vessels like Case 1. Both Japanese cases, who belonged to two separate families, had the same HK1 pathogenic mutation, with a phenotype of PPRCA. Futhermore, atrophy along retinal arteries was noted. Reviewing previous nonsyndromic RP79 cases revealed symptoms believed to be those of PPRCA. Ultra-widefield fundus imaging, especially ultra-widefield fundus autofluorescence, has been useful in detecting PPRCA. If these devices become widely available, more cases may be discovered in the future because PPRCA can be used as a clue to suspect RP79, and Sanger sequencing may be used to identify pathogenic mutations in HK1 at a lower cost and more easily than using whole-exome sequencing.
DOI: 10.6084/m9.figshare.24885303.v1
title: Supplementary Material for: Two Japanese Families with Pigmented Paravenous Retinochoroidal Atrophy and the HK1 Mutation: a Case Report

description: Hexokinase 1 (HK1) gene is the cause of autosomal dominant retinitis pigmentosa (RP) 79. To date, only the E874K mutation has been reported as the causative mutation in patients with non-syndromic RP. As a Caucasian RP case with a pathological variant of HK1 exhibiting pigmented paravenous retinochoroidal atrophy (PPRCA) phenotype was recently reported, we reviewed RP79 cases in our Japanese RP cohort. Consequently, two Japanese patients, who were diagnosed with RP79 by genetic tests in our RP cohort, were included in this study. Patient 1 was a 60-year-old woman. Fundus examination revealed symmetrical donut-shaped retinal degeneration, with pigment deposition avoiding the macula. Moreover, degeneration extended in a peripheral direction along the vessels like a starfish, and degeneration was observed around the veins and arteries. Patient 2 was a 75-year-old man. Fundus examination revealed symmetric macula-avoiding donut-shaped retinal degeneration, with paravenous protruding degeneration along the blood vessels like Case 1. Both Japanese cases, who belonged to two separate families, had the same HK1 pathogenic mutation, with a phenotype of PPRCA. Futhermore, atrophy along retinal arteries was noted. Reviewing previous nonsyndromic RP79 cases revealed symptoms believed to be those of PPRCA. Ultra-widefield fundus imaging, especially ultra-widefield fundus autofluorescence, has been useful in detecting PPRCA. If these devices become widely available, more cases may be discovered in the future because PPRCA can be used as a clue to suspect RP79, and Sanger sequencing may be used to identify pathogenic mutations in HK1 at a lower cost and more easily than using whole-exome sequencing.
DOI: 10.6084/m9.figshare.24873990
title: Supplementary Material for: Thymic innervation impairment in experimental autoimmune encephalomyelitis

description: The thymus is the primary lymphoid organ responsible for normal T-cell development. Yet, in abnormal metabolic conditions as well as an acute infection, the organ exhibits morphological and cellular alterations. It is well established that the immune system is in a tidy connection and dependent on the central nervous system (CNS), which regulates thymic function by means of innervation and neurotransmitters. Sympathetic innervation leaves the CNS and spreads through thymic tissue, where nerve endings interact directly or indirectly with thymic cells contributing to their maintenance and development. Herein, we hypothesized that brain damage due to an inflammatory process might elicit alterations upon the thymic-CNS neuroimmune axis, altering not just the sympathetic innervation and neurotransmitter release, but also modifying the thymus microenvironment and T cell development. We used the well-established multiple sclerosis model of experimental autoimmune encephalomyelitis (EAE), to study putative changes in the thymic neural, lymphoid, and microenvironmental compartments. We showed that along with EAE clinical development, thymus morphology, and cellular compartments are affected, altering the peripheric T cell population and modifying the retrograde thymic communication towards the CNS. Altogether, our data suggest that the thymic-CNS neuroimmune bidirectional axis is compromised in EAE. This imbalance may contribute to an increased and uncontrolled auto-immune reaction.
DOI: 10.6084/m9.figshare.24873990.v1
title: Supplementary Material for: Thymic innervation impairment in experimental autoimmune encephalomyelitis

description: The thymus is the primary lymphoid organ responsible for normal T-cell development. Yet, in abnormal metabolic conditions as well as an acute infection, the organ exhibits morphological and cellular alterations. It is well established that the immune system is in a tidy connection and dependent on the central nervous system (CNS), which regulates thymic function by means of innervation and neurotransmitters. Sympathetic innervation leaves the CNS and spreads through thymic tissue, where nerve endings interact directly or indirectly with thymic cells contributing to their maintenance and development. Herein, we hypothesized that brain damage due to an inflammatory process might elicit alterations upon the thymic-CNS neuroimmune axis, altering not just the sympathetic innervation and neurotransmitter release, but also modifying the thymus microenvironment and T cell development. We used the well-established multiple sclerosis model of experimental autoimmune encephalomyelitis (EAE), to study putative changes in the thymic neural, lymphoid, and microenvironmental compartments. We showed that along with EAE clinical development, thymus morphology, and cellular compartments are affected, altering the peripheric T cell population and modifying the retrograde thymic communication towards the CNS. Altogether, our data suggest that the thymic-CNS neuroimmune bidirectional axis is compromised in EAE. This imbalance may contribute to an increased and uncontrolled auto-immune reaction.
DOI: 10.6084/m9.figshare.24873690
title: Supplementary Material for: Primary peritoneal carcinosarcoma in a breast cancer patient harboring a germline BRCA2 pathogenic variant case report

description: Malignant mixed müllerian tumor (MMMT) is a rare neoplasm, consisting of carcinomatous (epithelial) and sarcomatous (mesenchymal) components that most commonly arise in the endometrium and more infrequently in the ovaries, fallopian tube, cervix, and vagina. Primary peritoneal carcinosarcoma (PPCS) is an extremely rare extragenital presentation of MMMT. Although the occurrence of breast cancer and epithelial ovarian carcinoma in association with BRCA pathogenic variants is firmly established, the etiologic role of these genes in the development of other tumor types is less well known. Here, we present a rare case of PPCS in a 42-year-old Brazilian woman with a BRCA2 pathogenic variant, c.2808_2811del (NM_000059.3). The patient developed metastatic breast cancer at the age of 37 and underwent a risk-reducing bilateral salpingo-oophorectomy two years later. She was then diagnosed with PPCS three years after the risk-reducing surgery. She underwent treatment with surgery, chemotherapy and targeted therapy but passed away almost five years after the second primary tumor diagnosis. To our knowledge, this is the first case of peritoneal carcinosarcoma described in a BRCA2 pathogenic variant carrier, and its report leads to a better understanding of the disease’s molecular features and possible therapeutic approaches.
DOI: 10.6084/m9.figshare.24873690.v2
title: Supplementary Material for: Primary peritoneal carcinosarcoma in a breast cancer patient harboring a germline BRCA2 pathogenic variant case report

description: Malignant mixed müllerian tumor (MMMT) is a rare neoplasm, consisting of carcinomatous (epithelial) and sarcomatous (mesenchymal) components that most commonly arise in the endometrium and more infrequently in the ovaries, fallopian tube, cervix, and vagina. Primary peritoneal carcinosarcoma (PPCS) is an extremely rare extragenital presentation of MMMT. Although the occurrence of breast cancer and epithelial ovarian carcinoma in association with BRCA pathogenic variants is firmly established, the etiologic role of these genes in the development of other tumor types is less well known. Here, we present a rare case of PPCS in a 42-year-old Brazilian woman with a BRCA2 pathogenic variant, c.2808_2811del (NM_000059.3). The patient developed metastatic breast cancer at the age of 37 and underwent a risk-reducing bilateral salpingo-oophorectomy two years later. She was then diagnosed with PPCS three years after the risk-reducing surgery. She underwent treatment with surgery, chemotherapy and targeted therapy but passed away almost five years after the second primary tumor diagnosis. To our knowledge, this is the first case of peritoneal carcinosarcoma described in a BRCA2 pathogenic variant carrier, and its report leads to a better understanding of the disease’s molecular features and possible therapeutic approaches.
DOI: 10.6084/m9.figshare.24873690.v1
title: Supplementary Material for: Primary peritoneal carcinosarcoma in a breast cancer patient harboring a germline BRCA2 pathogenic variant case report

description: Malignant mixed müllerian tumor (MMMT) is a rare neoplasm, consisting of carcinomatous (epithelial) and sarcomatous (mesenchymal) components that most commonly arise in the endometrium and more infrequently in the ovaries, fallopian tube, cervix, and vagina. Primary peritoneal carcinosarcoma (PPCS) is an extremely rare extragenital presentation of MMMT. Although the occurrence of breast cancer and epithelial ovarian carcinoma in association with BRCA pathogenic variants is firmly established, the etiologic role of these genes in the development of other tumor types is less well known. Here, we present a rare case of PPCS in a 42-year-old Brazilian woman with a BRCA2 pathogenic variant, c.2808_2811del (NM_000059.3). The patient developed metastatic breast cancer at the age of 37 and underwent a risk-reducing bilateral salpingo-oophorectomy two years later. She was then diagnosed with PPCS three years after the risk-reducing surgery. She underwent treatment with surgery, chemotherapy and targeted therapy but passed away almost five years after the second primary tumor diagnosis. To our knowledge, this is the first case of peritoneal carcinosarcoma described in a BRCA2 pathogenic variant carrier, and its report leads to a better understanding of the disease’s molecular features and possible therapeutic approaches.
DOI: 10.6084/m9.figshare.24826686
title: Supplementary Material for: Turpentine ointment for the treatment of folliculitis – an open, prospective, randomized, placebo- and comparator-controlled multicenter trial

description: Introduction: Folliculitis is a painful infection and inflammation of hair follicles, mostly caused by bacterial, fungal or, more rarely, viral infections. Turpentine derivatives have been used traditionally to treat various skin infections and could thus also be effective in treating folliculitis. We carried out an open, prospective, randomized, placebo- and comparator-controlled multicenter trial to evaluate the efficacy and safety of an ointment containing pine turpentine oil, larch turpentine, and eucalyptus oil in the treatment of acute folliculitis. Methods: 70 outpatients with acute folliculitis were treated with the turpentine ointment, a comparator (povidone iodine solution), or a placebo (Vaseline) for 7 days. Photographs of the affected skin areas were taken by the physicians at four visits, and by the patients on a daily basis. Photographs were evaluated by blinded observers. Primary efficacy endpoint was the change in total hair follicle lesion counts. Secondary endpoints included the evolution of the lesion counts in the course of the study, responder rate (improvement of follicle lesions by at least one count), and the patient’s global assessment. Safety endpoints were the tolerability of the treatments and adverse events recording. Results: A decrease of follicle lesions counts was detected for both active treatments, but not for placebo, but the differences among groups were not statistically significant. As for the secondary endpoints, the ointment showed statistically significant superiority over placebo for the evolution of the lesions during the course of the study (p=0.017), the responder rate (p=0.032), and the subjective efficacy assessment by patients (p=0.029). All treatments were equally well tolerated, with a similar number of treatment-emergent adverse events. Conclusion: The turpentine ointment is an effective and safe option for the treatment of folliculitis.
DOI: 10.5281/zenodo.10066543
title: The first 500-meter, long-term winter wheat grain protein content dataset for China from multi-source data

description: In China, the demand for precise perception of wheat Grain Protein Content (GPC) has gained increased urgency, driven by the rising demands in the food consumption market and intensifying international market competition. However, due to the lack of extensive, prolonged high-resolution benchmark data, previous GPC studies have primarily focused on experimental fields, small geographic units, and limited temporal scopes. Additionally, the diversified geographical landscape in China introduces spatiotemporal heterogeneity and intricacy to the influence of wheat GPC, further amplifying the challenges of large-scale GPC estimation. To address this challenge and the data gap, the first 500-meter spatial resolution, long-term winter wheat dataset covering major planting regions in China (CNWheatGPC-500) was created by integrating multi-source data from ERA5 and MODIS.