Chemotherapeutic agents cause many short and long term toxic side effects to peripheral nervous system (PNS) that drastically alter quality of life. Chemotherapy-induced peripheral neuropathy (CIPN) ...is a common and enduring disorder caused by several anti-neoplastic agents. CIPN typically presents with neuropathic pain, numbness of distal extremities, and/or oversensitivity to thermal or mechanical stimuli. This adverse side effect often requires a reduction in chemotherapy dosage or even discontinuation of treatment. Currently there are no effective treatment options for CIPN. While the underlying mechanisms for CIPN are not understood, current data identify a "dying back" axon degeneration of distal nerve endings as the major pathology in this disorder. Therefore, mechanistic understanding of axon degeneration will provide insights into the pathway and molecular players responsible for CIPN. Here, we review recent findings that expand our understanding of the pathogenesis of CIPN and discuss pathways that may be shared with the axonal degeneration that occurs during developmental axon pruning and during injury-induced Wallerian degeneration. These mechanistic insights provide new avenues for development of therapies to prevent or treat CIPN.
Background Human reproduction depends on the fusion of a mature oocyte with a sperm cell to form a fertilized egg. The genetic events that lead to the arrest of human oocyte maturation are unknown. ...Methods We sequenced the exomes of five members of a four-generation family, three of whom had infertility due to oocyte meiosis I arrest. We performed Sanger sequencing of a candidate gene, TUBB8, in DNA samples from these members, additional family members, and members of 23 other affected families. The expression of TUBB8 and all other β-tubulin isotypes was assessed in human oocytes, early embryos, sperm cells, and several somatic tissues by means of a quantitative reverse-transcriptase-polymerase-chain-reaction assay. We evaluated the effect of the TUBB8 mutations on the assembly of the heterodimer consisting of one α-tubulin polypeptide and one β-tubulin polypeptide (α/β-tubulin heterodimer) in vitro, on microtubule architecture in HeLa cells, on microtubule dynamics in yeast cells, and on spindle assembly in mouse and human oocytes. Results We identified seven mutations in the primate-specific gene TUBB8 that were responsible for oocyte meiosis I arrest in 7 of the 24 families. TUBB8 expression is unique to oocytes and the early embryo, in which this gene accounts for almost all the expressed β-tubulin. The mutations affect chaperone-dependent folding and assembly of the α/β-tubulin heterodimer, disrupt microtubule behavior on expression in cultured cells, alter microtubule dynamics in vivo, and cause catastrophic spindle-assembly defects and maturation arrest on expression in mouse and human oocytes. Conclusions TUBB8 mutations have dominant-negative effects that disrupt microtubule behavior and oocyte meiotic spindle assembly and maturation, causing female infertility. (Funded by the National Basic Research Program of China and others.).
Translocated saltwater crocodiles (Crocodylus porosus) in the Northern Territory (NT) of Australia often return to their original capture sites, which complicates management interventions aimed at ...reducing human-crocodile conflict. We examined the spatial events implicated in this homing ability, using ARGOS satellite tracking devices. Five large male C. porosus (3.03 m to 4.02 m TL) were shifted and released 100-320 km from their capture sites, and 3 additional ones (3.67 m to 4.23 m TL) were released at their site of capture as controls. Translocated crocodiles were more mobile than the controls, and moved at sea in the direction of their original capture site. However, they were unable or unwilling to swim around a geographic structure, Cobourg Peninsula, which prevented homing being achieved in all five cases. Two control crocodiles remained near their capture sites, but one, after the first year, made a 900km journey for six months, before returning to its original capture and release site. Genetic analysis of tissue samples from nests across the NT coast demonstrated significant genetic structure across the coast, and confirmed that Cobourg Peninsula contributes to genetic differentiation among populations along the NT coast. These results provide new insights into C. porosus movements, which have management significance for the maintenance of public safety.
Abstract
Cyclic electron transfer (CET) predominates when NADP
+
is at basal levels, early in photosynthetic induction; however, the mechanism underlying the subsequent supply of NADP
+
to fully ...drive steady-state linear electron transfer remains unclear. Here, we investigated whether CET is involved in de novo NADP
+
supply in
Arabidopsis thaliana
and measured chloroplastic NADP dynamics to evaluate responsiveness to variable light, photochemical inhibitors, darkness, and CET activity. The sum of oxidized and reduced forms shows that levels of NADP and NAD increase and decrease, respectively, in response to light; levels of NADP and NAD decrease and increase in the dark, respectively. Moreover, consistent with the pH change in the stroma, the pH preference of chloroplast NAD
+
phosphorylation and NADP
+
dephosphorylation is alkaline and weakly acidic, respectively. Furthermore, CET is correlated with upregulation of light-responsive NADP level increases and downregulation of dark-responsive NADP level reductions. These findings are consistent with CET helping to regulate NADP pool size via stromal pH regulation under fluctuating light conditions.
Chronic endometritis (CE), an inflammatory condition characterized by plasma cell infiltration within the endometrial stroma, is prevalent among women experiencing unexplained infertility or ...recurrent miscarriages. CE is traditionally diagnosed by endometrial biopsy using CD138 immunohistochemistry staining. Despite some studies suggesting hysteroscopy as an alternative diagnostic tool, its reliability compared with biopsy remains controversial. This study evaluated the diagnostic accuracy of hysteroscopy for CE by examining endometrial features, such as congestion, micropolyps, edema, and polyps, and comparing these with biopsy-confirmed cases of CE. This retrospective observational study was conducted at Toho University Omori Medical Center between June 2017 and November 2019 and included patients undergoing both hysteroscopy and histopathological examination. Endometrial congestion was identified as the only hysteroscopic finding significantly associated with CE, showing a moderate diagnostic agreement with biopsy results. These findings highlight the importance of further investigating hysteroscopic features of CE and their diagnostic implications and identify endometrial congestion as a potential predictive marker for CE.
Conflicts between humans and crocodilians are a widespread conservation challenge and the number of crocodile attacks is increasing worldwide. We identified the factors that most effectively decide ...whether a victim is injured or killed in a crocodile attack by fitting generalized linear models to a 42-year dataset of 87 attacks (27 fatal and 60 non-fatal) by saltwater crocodiles (Crocodylus porosus) in Australia. The models showed that the most influential factors were the difference in body mass between crocodile and victim, and the position of victim in relation to the water at the time of an attack. In-water position (for diving, swimming, and wading) had a higher risk than on-water (boating) or on-land (fishing, and hunting near the water's edge) positions. In the in-water position a 75 kg person would have a relatively high probability of survival (0.81) if attacked by a 300 cm crocodile, but the probability becomes much lower (0.17) with a 400 cm crocodile. If attacked by a crocodile larger than 450 cm, the survival probability would be extremely low (<0.05) regardless of the victim's size. These results indicate that the main cause of death during a crocodile attack is drowning and larger crocodiles can drag a victim more easily into deeper water. A higher risk associated with a larger crocodile in relation to victim's size is highlighted by children's vulnerability to fatal attacks. Since the first recently recorded fatal attack involving a child in 2006, six out of nine fatal attacks (66.7%) involved children, and the average body size of crocodiles responsible for these fatal attacks was considerably smaller (384 cm, 223 kg) than that of crocodiles that killed adults (450 cm, 324 kg) during the same period (2006-2014). These results suggest that culling programs targeting larger crocodiles may not be an effective management option to improve safety for children.
The relationship between the number of nurses in psychiatric wards and frequency of use of seclusion and restraint has been unclear. We aimed to clarify this relationship in Japanese general ...psychiatric wards while controlling for patient and ward-level characteristics. We hypothesized that seclusion and mechanical restraint are less likely to be used in a ward with more nurses. We used data for individual admissions from April 2015 to March 2017 in hospitals participating in the Psychiatric Electronic Clinical Observation (PECO) system, which extracted data from each hospital's electronic health record system. We analyzed the data of 10,013 admissions in 113 wards of 23 hospitals. We examined the relationships between the number of nurses per 10 beds in each ward and the use of seclusion and mechanical restraint, controlling for the patients' age, sex, diagnosis, voluntary versus involuntary admission, prescribed dose of antipsychotics, severity of symptoms, and length of stay, in addition to ward-level characteristics including ward size, location (urban or rural), and type of ward (acute ward or not), using multilevel multivariate logistic regression analyses. The fraction of admissions exposed to at least one episode of seclusion or mechanical restraint was 36.7% and 14.9%, respectively. The odds ratios of the number of nurses per 10 beds for the use of seclusion and mechanical restraint were 2.36 and 1.74, respectively, indicating that both seclusion and mechanical restraint were actually used more frequently in wards with more nurses. A possible explanation is that patients anticipated to need coercive measures are more likely to be admitted to wards with many nurses. Increasing the number of nurses in a ward may not contribute to reducing the use of seclusion and restraint.
Climate change is predicted to have devastating impacts on apex predators such as eliminating their required habitats. Crocodilians are no exception as most species require freshwater for nesting, ...and such freshwater habitats are particularly vulnerable to saltwater inundation (SWI) caused by the sea level rise (SLR) from global warming. Here, we examined the impacts of climate change on saltwater crocodiles
Crocodylus porosus
in terms of the potential loss of nesting habitat in the Northern Territory, Australia; an area that contains the world’s most extensive nesting habitat for the species. Our spatial model, derived from 730 nest locations and selected environmental features, estimated a total of 32,306.91 km
2
of current suitable habitat across the study region. The most important variable was distance to perennial lakes (71.0% contribution, 87.5% permutation importance), which is negatively correlated with nesting habitat suitability. We found that projected changes in temperature and rainfall by 2100 could impact the area of suitable nesting habitat negatively or positively (0.33% decrease under low future emission climate scenario, and 32.30% increase under high emission scenario). Nevertheless, this can be canceled by the strong negative impact of SLR and concomitant SWI on nesting areas. A portion (16.40%) of the modeled suitable habitat for a subsection of our study area, the Kakadu Region, were already subject to > 0.25 m SWI in 2013. The suitable area for nesting in this region is predicted to be further reduced to 1775.70 km
2
with 1.1 m SLR predicted for 2100, representing 49.81% loss between 2013 and 2100. Although the estimates of habitat loss do not account for the potential creation of new habitat, nor for the uncertainty in the degree of future SLR, our results suggest that SLR driven by continuing global warming can be the major threat to mound-nest-building crocodilians including
C. porosus
, rather than direct impacts from changes in temperature and rainfall. The degree of impact on saltwater crocodiles will be determined by the interplay between the loss of nesting habitat, which would appear inevitable under current global warming, and the ability to expand into new areas created by the expansion of the tropics.
On the IUCN Red List the saltwater crocodile Crocodylus porosus is categorized globally as Least Concern, with national populations ranging from fully recovered to extinct. The saltwater crocodile ...population of the Southeast Asian island nation of Timor-Leste was severely depleted by colonial hunting but has recovered since independence in 2002. During 2007–2014 there was a 23-fold increase in reported crocodile attacks (104 documented attacks), concomitant with a 2% annual increase in the human population. Public tolerance to attacks and the reluctance to harm crocodiles are entwined with reverence of crocodiles as sacred beings by most but not all Timorese people. In 2022, 7–8 years after our previous assessment, we visited five sites on the south coast of Timor-Leste in Lautém, Viqueque, Manufahí and Cova Lima municipalities. High rates of crocodile attacks continue. We obtained 35 records of attacks for 2015–2022 (34% fatal). In the municipalities where crocodile attacks occurred (Lautém, Viqueque, Cova Lima), the sacred status of crocodiles prevented inhabitants from harming them in retribution. In Manufahí, where no attacks were reported, such traditional values never existed and crocodiles were hunted for subsistence and to improve safety. The design of a context-specific crocodile management programme that respects the reverence attributed to crocodiles by most people but reduces the risk of people being attacked by crocodiles is a conservation management challenge for the government of Timor-Leste. The developing tourism industry, which relies on coastal beaches and reefs, is jeopardized by the risk of crocodile attacks.
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