Core-shell hydrogel microfiber-expanded pluripotent stem cell-derived lung progenitors applicable to lung reconstruction in vivo

ヒトiPS細胞由来肺前駆細胞の拡大培養とマウス肺への移植・生着に成功 --肺再生医療の実現へ大きな一歩--. 京都大学プレスリリース. 2021-07-30.Lung transplantation is the only treatment available for end-stage lung diseases; however, donor shortage is a global issue. The use of human pluripotent stem cells (hPSCs) for organ regeneration is a promising approach. Nevertheless, methods for the expansion of isolated hPSC-derived lung progenitors (hLPs) for transplantation purposes have not yet been reported. Herein, we established an expansion system of hLPs based on their three-dimensional culture in core-shell hydrogel microfibers, that ensures the maintenance of their bipotency for differentiation into alveolar and airway epithelial cells including alveolar type II (AT2) cells. Further, we developed an efficient in vivo transplantation method using an endoscope-assisted transtracheal administration system; the successful engraftment and in vivo differentiation of hLPs into alveolar epithelial cells (incorporated into the alveoli) was observed. Importantly, expanded hLPs in the context of microfibers were successfully transplanted into the murine lungs, opening avenues for cell-based therapies of lung diseases. Therefore, our novel method has potential regenerative medicine applications; additionally, the high-quality hLPs and AT2 cells generated via the microfiber-based technology are valuable for drug discovery purposes

Functional expansion of a TCA cycle operon mRNA by a 3′ end-derived small RNA

Global RNA profiling studies in bacteria have predicted the existence of many of small noncoding RNAs (sRNAs) that are processed off mRNA 3′ ends to regulate other mRNAs via the RNA chaperones Hfq and ProQ. Here, we present targets of SdhX (RybD), an Hfq-dependent sRNA that is generated by RNase E mediated 3′ processing of the ∼10 000-nt mRNA of the TCA cycle operon sdhCDAB-sucABCD in enteric bacteria. An in silico search predicted ackA mRNA, which encodes acetate kinase, as a conserved primary target of SdhX. Through base pairing, SdhX represses AckA synthesis during growth of Salmonella on acetate. Repression can be achieved by a naturally occurring 38-nucleotide SdhX variant, revealing the shortest functional Hfq-associated sRNA yet. Salmonella SdhX also targets the mRNAs of fumB (anaerobic fumarase) and yfbV, a gene of unknown function adjacent to ackA. Instead, through a slightly different seed sequence, SdhX can repress other targets in Escherichia coli, namely katG (catalase) and fdoG (aerobic formate dehydrogenase). This study illustrates how a key operon from central metabolism is functionally connected to other metabolic pathways through a 3′ appended sRNA, and supports the notion that mRNA 3′UTRs are a playground for the evolution of regulatory RNA networks in bacteria

Importin-β and the small guanosine triphosphatase Ran mediate chromosome loading of the human chromokinesin Kid

Nucleocytoplasmic transport factors mediate various cellular processes, including nuclear transport, spindle assembly, and nuclear envelope/pore formation. In this paper, we identify the chromokinesin human kinesin-like DNA binding protein (hKid) as an import cargo of the importin-α/β transport pathway and determine its nuclear localization signals (NLSs). Upon the loss of its functional NLSs, hKid exhibited reduced interactions with the mitotic chromosomes of living cells. In digitonin-permeabilized mitotic cells, hKid was bound only to the spindle and not to the chromosomes themselves. Surprisingly, hKid bound to importin-α/β was efficiently targeted to mitotic chromosomes. The addition of Ran–guanosine diphosphate and an energy source, which generates Ran–guanosine triphosphate (GTP) locally at mitotic chromosomes, enhanced the importin-β–mediated chromosome loading of hKid. Our results indicate that the association of importin-β and -α with hKid triggers the initial targeting of hKid to mitotic chromosomes and that local Ran-GTP–mediated cargo release promotes the accumulation of hKid on chromosomes. Thus, this study demonstrates a novel nucleocytoplasmic transport factor–mediated mechanism for targeting proteins to mitotic chromosomes

Efficacy of Combination Therapy with Telmisartan Plus Amlodipine in Patients with Poorly Controlled Hypertension

There is accumulating evidence that blood pressure (BP) control significantly reduces the risk of future cardiovascular events in patients with essential hypertension. However, strict BP control is often difficult to maintain, and half of hypertensive patients fail to attain BP goals on single-drug therapy. Therefore, current guidelines recommend combinations of drugs that have complimentary mode of actions for treatment of patients with moderate hypertension. In this study, we examined in hypertensive patients uncontrolled by the combination treatment with 5 mg amlodipine plus 80 mg valsartan or 8 mg candesartan whether additional BP lowering could be achieved by switching to 5 mg amlodipine plus 40 mg telmisartan. Forty-seven patients with essential hypertension who failed to achieve a target BP level by the treatment of 5 mg amlodipine plus 80 mg valsartan or 8 mg candesartan for at least 2 months were enrolled. Replacement of valsartan or candesartan by telmisartan showed a significant reduction in both mean clinic systolic and diastolic BP at 4, 8 and 12 weeks; BP level decreased from 143.7/82.3 mmHg at baseline to 135.4/77.5 mmHg at 12 weeks. Furthermore, in 8 patients of valsartan group, switching to telmisartan significantly reduced central BP by 11.8 mmHg. Our present study suggests that combination therapy with telmisartan plus amlodipine may be more beneficial than valsartan or candesartan plus amolodipine treatment for controlling brachial and central BP, which could lead to more favorable cardiovascular outcomes with this drug combinations

Clinical trials for drug approval : a pilot study of the view of doctors at Tokushima University Hospital

The development of new and useful pharmaceutical drugs is essential in order to improve the quality of drug therapeutics. Clinical trials play a central role in drug development. Over time, the clinical trial infrastructure has improved and is now integrating the contribution of clinical research coordinators (CRC). Nevertheless, the attitude of doctors towards clinical trials still favors conventional/historical methodologies. In the present study, we explored the view of doctors towards clinical trials for drug development, in order to improve communication among participants, sponsors, and investigators. A questionnaire was designed for this pilot study. The questionnaire included general attitudes, difficult points, the benefit of doctors in participating as investigators, special attention requirements, and the expected role of CRC in clinical trials for drug approval. In addition, the appropriate use of the outpatient clinic was examined. The questionnaire was provided to doctors in each department of Tokushima University Hospital in 2000 and 2004. Because of the small number of subjects included in this pilot study, no statistical analysis is presented. A total of 89 (81%) and62 (56%) doctors among 110 responded to the survey in 2000 and 2004, respectively. Inquiries about the familiarity of the physicians with clinical trials for drug approval revealed that 84% in 2000 and 66% in 2004 were aware of such trials. The attitude towards participating as investigators in the clinical trials was favorable, with a response of 66% in 2000 and 58% in 2004. Patients’ refusal and the informed consent process were considered difficult areas by many doctors. Expected roles of CRC included activities based on the nurse’s specialty. Although many doctors agreed to take care of the study participants separately from the clinical practice, they lacked the time to do so. In spite of the doctors’ workload reduction by introduction of the CRC concept, their views regarding clinical trials for drug approval remain conventional. Further refinement in the support process by CRC should be considered in our hospital, and the views of the doctors should be investigated in a larger study, in order to promote clinical trials for drug approval in Japan

'Productus compressus' Waagen, 1884 (currently 'Compressoproductus compressus'; Brachiopoda): proposed conservation of the specific name

The purpose of this application, under Articles 23.9.3 and 81.2.1 of the Code, is to conserve the specific name 'Productus compressus' Waagen, 1884 for the type species of the Permian brachiopod genus 'Compressoproductus' Sarytcheva in Sarytcheva et al., 1960. The name is a junior primary homonym of 'Productus compressus' Say in James, 1823, which has been seldom used since it was established. Waterhouse & Piyasin (1970) proposed 'Compressoproductus morahpressus' as a substitute name for Productus compressus Waagen, 1884, but this name has never been used other than by Waterhouse (1978, 1983). It is proposed that the name 'Productus compressus' Waagen, 1884 be conserved by suppression of 'Productus compressus' Say, 1823

Case 3352. Productus compressus Waagen, 1884 (currently Compressoproductus Compressus; Brachiopoda): proposed conservation of the specific name

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Late Permian (Changhsingian) and Early Triassic (Induan) conodonts and the Permian-Triassic boundary in central Peninsular Malaysia

The Permian-Triassic boundary (PTB) is defined in the GSSP section at Meishan, China at the base of Bed 27c and is recognised by the first appearance of the conodont 'Hindeoudus parvus'. The PTB is dated at 252.3 Ma by bracketing tuff CA-IDTIMS ages and is slightly younger than the main "end" Permian (late Changhsingian) mass extinction. Despite decades of searching, the PTB has not been located precisely to date in Malaysia and it is still unclear if a stratigraphic break occurs at the boundary. In central Peninsula Malaysia, there are three mogote hill limestone sections, Gua Panjang, Gua Bama and Gua Sei, that have yielded biostratigraphic data indicating the probably presence of the PTB. The Late Permian foraminifers 'Palaeofusulina' and 'Colaniella', which indicate a probable Changhsingian (but not latest Changhsingian) age have been reported from the lower parts of Gua Panjang and Gua Sei. Changhsingian conodonts including 'Clarkina' spp., 'Hindeodus julfensis' and 'Hindeodus typicalis', occur in the lowest part of the Gua Panjang by the presence of the Early Triassic has not yet been confirmed

A Permian phillipsiid trilobite from Peninsular Malaysia

Pygidia of the trilobite 'Pseudophillipsia' sp. are reported from the Permian Bera Formation, Pahang, Peninsular Malaysia, in association with a moderately rich brachiopod fauna of early Capitanian (Guadalupian) age. It resembles a slightly younger Capitanian species 'Pseudophillipsia acuminata' Mansuy, 1912 of northern laos. This find suggests an additional faunal link between Indochina and Peninsular Malaysia (the East Malaya terrane) during Capitanian time