Bellwethers of change: population modelling of North Pacific humpback whales from 2002 through 2021 reveals shift from recovery to climate response.

For the 40 years after the end of commercial whaling in 1976, humpback whale populations in the North Pacific Ocean exhibited a prolonged period of recovery. Using mark-recapture methods on the largest individual photo-identification dataset ever assembled for a cetacean, we estimated annual ocean-basin-wide abundance for the species from 2002 through 2021. Trends in annual estimates describe strong post-whaling era population recovery from 16 875 (± 5955) in 2002 to a peak abundance estimate of 33 488 (± 4455) in 2012. An apparent 20% decline from 2012 to 2021, 33 488 (± 4455) to 26 662 (± 4192), suggests the population abruptly reached carrying capacity due to loss of prey resources. This was particularly evident for humpback whales wintering in Hawai'i, where, by 2021, estimated abundance had declined by 34% from a peak in 2013, down to abundance levels previously seen in 2006, and contrasted to an absence of decline in Mainland Mexico breeding humpbacks. The strongest marine heatwave recorded globally to date during the 2014-2016 period appeared to have altered the course of species recovery, with enduring effects. Extending this time series will allow humpback whales to serve as an indicator species for the ecosystem in the face of a changing climate.

Transaminases Provide Key Chiral Building Blocks for the Synthesis of Selective M1/M4 Agonists.

We have developed a chiral route toward the synthesis of muscarinic M4 agonists that was enabled by the biocatalytic synthesis of the key spirocyclic diamine building blocks 10 and 12. Using these bifunctional compounds we were able to optimize a synthetic sequence toward a collection of advanced intermediates for further elaboration. These advanced intermediates were then used as starting points for early medicinal chemistry and the identification of selective M1/M4 agonists.

The Lysosomal Calcium Channel TRPML1 Maintains Mitochondrial Fitness in NK Cells through Interorganelle Cross-Talk.

Cytotoxic lymphocytes eliminate cancer cells through the release of lytic granules, a specialized form of secretory lysosomes. This compartment is part of the pleomorphic endolysosomal system and is distinguished by its highly dynamic Ca2+ signaling machinery. Several transient receptor potential (TRP) calcium channels play essential roles in endolysosomal Ca2+ signaling and ensure the proper function of these organelles. In this study, we examined the role of TRPML1 (TRP cation channel, mucolipin subfamily, member 1) in regulating the homeostasis of secretory lysosomes and their cross-talk with mitochondria in human NK cells. We found that genetic deletion of TRPML1, which localizes to lysosomes in NK cells, led to mitochondrial fragmentation with evidence of collapsed mitochondrial cristae. Consequently, TRPML1-/- NK92 (NK92ML1-/-) displayed loss of mitochondrial membrane potential, increased reactive oxygen species stress, reduced ATP production, and compromised respiratory capacity. Using sensitive organelle-specific probes, we observed that mitochondria in NK92ML1-/- cells exhibited evidence of Ca2+ overload. Moreover, pharmacological activation of the TRPML1 channel in primary NK cells resulted in upregulation of LC3-II, whereas genetic deletion impeded autophagic flux and increased accumulation of dysfunctional mitochondria. Thus, TRPML1 impacts autophagy and clearance of damaged mitochondria. Taken together, these results suggest that an intimate interorganelle communication in NK cells is orchestrated by the lysosomal Ca2+ channel TRPML1.

Mapping the chemotactic landscape in NK cells reveals subset-specific synergistic migratory responses to dual chemokine receptor ligation.

BACKGROUND: Natural killer (NK) cells have a unique capability of spontaneous cytotoxicity against malignant cells and hold promise for off-the-shelf cell therapy against cancer. One of the key challenges in the field is to improve NK cell homing to solid tumors. METHODS: To gain a deeper understanding of the cellular mechanisms regulating trafficking of NK cells into the tumor, we used high-dimensional flow cytometry, mass cytometry, and single-cell RNA-sequencing combined with functional assays, creating a comprehensive map of human NK cell migration phenotypes. FINDINGS: We found that the chemokine receptor repertoire of peripheral blood NK cells changes in a coordinated manner becoming progressively more diversified during NK cell differentiation and correlating tightly with the migratory response of the distinct NK cell subsets. Simultaneous ligation of CXCR1/2 and CX3CR1, synergistically potentiated the migratory response of NK cells. Analysis of 9471 solid cancers from publicly available TCGA/TARGET repositories revealed dominant chemokine patterns that varied across tumor types but with no tumor group expressing ligands for more than one chemokine receptor present on mature NK cells. INTERPRETATION: The finding that chemokine stimulation can elicit a synergistic migratory response in NK cells combined with the identified lack of naturally occurring pairs of chemokines-chemokine receptors in human cancers may explain the systematic exclusion of NK cells from the tumor microenvironment and provides a basis for engineering next-generation NK cell therapies against malignancies. FUNDING: The Polish Ministry of Science and Higher Education, the National Science Centre, Poland, The Norwegian Cancer Society, the Norwegian Research Council, the South-Eastern Norway Regional Health Authority, The Swedish Cancer Society, the Swedish Children's Cancer Foundation, The Swedish Research Council, The Center of Excellence: Precision Immunotherapy Alliance, Knut and Alice Wallenberg Foundation and National Cancer Institute.

Impacts of marine heatwaves on top predator distributions are variable but predictable.

Marine heatwaves cause widespread environmental, biological, and socio-economic impacts, placing them at the forefront of 21st-century management challenges. However, heatwaves vary in intensity and evolution, and a paucity of information on how this variability impacts marine species limits our ability to proactively manage for these extreme events. Here, we model the effects of four recent heatwaves (2014, 2015, 2019, 2020) in the Northeastern Pacific on the distributions of 14 top predator species of ecological, cultural, and commercial importance. Predicted responses were highly variable across species and heatwaves, ranging from near total loss of habitat to a two-fold increase. Heatwaves rapidly altered political bio-geographies, with up to 10% of predicted habitat across all species shifting jurisdictions during individual heatwaves. The variability in predicted responses across species and heatwaves portends the need for novel management solutions that can rapidly respond to extreme climate events. As proof-of-concept, we developed an operational dynamic ocean management tool that predicts predator distributions and responses to extreme conditions in near real-time.

Migratory destinations and spatial structuring of humpback whales (Megaptera novaeangliae) wintering off Nicaragua.

Understanding the migratory patterns of large whales is of conservation importance, especially in identifying threats to specific populations. Migration ecology, including migratory destinations, movements and site fidelity for humpback whales (Megaptera novaeangliae) remain poorly studied in parts of the range of the Central America population, considered endangered under the United States Endangered Species Act. This study aimed to investigate the migratory destinations of humpback whales sighted at two study sites in Nicaragua, which are part of the Central America population. A ten-year photographic database of humpback whales observed off Nicaragua was combined with citizen science contributions and sightings from dedicated research programs. The resulting image collection was compared with available historical photo identifications and databases using an automated image recognition algorithm. This approach yielded 36 years of photographic identification totaling 431 recaptures in Nicaragua (2006-2008 and 2016-2021) and 2539 recaptures (1986-2020) in both feeding and breeding grounds of 176 unique individuals sighted in Nicaragua. Our results showed that photo-identified whales were recaptured between October and April in breeding grounds and year-round in feeding grounds between British Columbia and California, with peak recaptures between June and October. Our study provided first-time evidence on fine-scale site affinity of individual humpback whales within Nicaraguan waters and to other breeding and feeding grounds.

A collaborative and near-comprehensive North Pacific humpback whale photo-ID dataset.

We present an ocean-basin-scale dataset that includes tail fluke photographic identification (photo-ID) and encounter data for most living individual humpback whales (Megaptera novaeangliae) in the North Pacific Ocean. The dataset was built through a broad collaboration combining 39 separate curated photo-ID catalogs, supplemented with community science data. Data from throughout the North Pacific were aggregated into 13 regions, including six breeding regions, six feeding regions, and one migratory corridor. All images were compared with minimal pre-processing using a recently developed image recognition algorithm based on machine learning through artificial intelligence; this system is capable of rapidly detecting matches between individuals with an estimated 97-99% accuracy. For the 2001-2021 study period, a total of 27,956 unique individuals were documented in 157,350 encounters. Each individual was encountered, on average, in 5.6 sampling periods (i.e., breeding and feeding seasons), with an annual average of 87% of whales encountered in more than one season. The combined dataset and image recognition tool represents a living and accessible resource for collaborative, basin-wide studies of a keystone marine mammal in a time of rapid ecological change.

Drug Hunting at the Nexus of Medicinal Chemistry and Chemical Biology and the Discovery of Novel Therapeutic Modalities.

Small molecules designed to modulate protein function have been remarkably successful in advancing human health. As the frontiers of medicine and understanding of disease pathogenesis continue to expand, small molecule scientists must also pursue the development of novel therapeutic modalities beyond functional protein modulation to address diseases of unmet medical need. In this vein, this Perspective will highlight two emerging modalities, selective mRNA splice modulation and targeted protein degradation, as mechanisms that affect protein abundance, rather than protein function, to broaden the scope of low-molecular-weight treatable diseases. Key to the elucidation and development of these mechanisms was the interplay and contemporaneous efforts in medicinal chemistry and chemical biology. Continued research at the intersection of these two fields will be critical for the identification of novel targets and mechanisms toward the development of the next generation of small molecule therapeutics.

Incidence and Trend of Type I and II Endometrial Cancer in Women from Two Population-Based European Cancer Registries (1998-2012).

Endometrial cancer (EC) is the most frequent female genital tract cancer in Europe. This cohort study aimed to determine age-standardised incidence rates and long-term trends of type I and II endometrial cancer in women from population-based cancer registries in the Region of Murcia (Spain) and the Bas-Rhin area (France). Data of new cases of endometrial cancer between 1998 and 2012 were obtained from the Murcia and Bas-Rhin cancer registries. In that period, 3756 cases of endometrial cancer were recorded, with 3270 corresponding to type I EC and 486 corresponding to type II EC. The Bas-Rhin area presented higher age-adjusted incidence rates than those in the Region of Murcia for both type I EC (24.2 and 19.3 cases/100,000 person-years (py), respectively) and type II EC (4.4 and 2.3 cases/100,000 py, respectively). Joinpoint regression showed no changes in trends. In both populations, there was an increasing trend for both EC types, but the trend was steeper in the Region of Murcia and larger overall for type II EC. Finally, a significant increase was observed in the annual trend of type II EC. Further studies are warranted to determine the potential risk factors, and continued efforts are needed to improve the recording and monitoring of EC types.

An optimized platform for efficient siRNA delivery into human NK cells.

The molecular networks that regulate natural killer (NK) cell functions are not completely understood. Here, we present a workflow for efficient delivery of siRNA into human NK cells without compromising viability. This methodology represents a promising approach for rapidly interrogating gene functions in primary human NK cells.

Efficacy and Safety of Ivermectin and Hydroxychloroquine in Patients with Severe COVID-19: A Randomized Controlled Trial.

During the first year of the COVID-19 pandemic, unauthorized drugs were widely used. Ivermectin and hydroxychloroquine are drugs that inhibit viral replication in vitro and that have been used in several medical centers. This clinical trial analyzes their efficacy in hospitalized patients with moderate COVID-19. Methods: This a controlled, clinical, randomized, double-blind trial that included hospitalized patients with COVID-19-induced pneumonia, without severe respiratory failure. Patients were randomized to one of three groups: Group 1-hydroxychloroquine, 400 mg every 12 h on the first day and, subsequently, 200 mg every 12 h for 4 days; Group 2-ivermectin, 12 mg or 18 mg, according to patient weight; and Group 3-placebo. At inclusion, blood samples for arterial blood gases and biochemical markers were obtained. The primary outcome was established as the length of stay due to patient improvement and the rate of respiratory deterioration or death. Results: During the month of August 2020, the admission of patients requiring hospitalization mostly encompassed cases with severe respiratory failure, so we ended the recruitment process and analyzed the data that was available at the time. One hundred and six (106) patients with an average age of 53 yrs (±16.9) were included, with a greater proportion of males (n = 66, 62.2%). Seventy-two percent (72%) (n = 76) had an associated comorbidity. Ninety percent (90%) of patients were discharged due to improvement (n = 96). The average duration of hospitalization was 6 days (IQR, 3-10). No difference in hospitalization duration was found between the treatment groups (Group1: 7 vs. Group 2: 6 vs. Group 3: 5, p = 0.43) nor in respiratory deterioration or death (Group 1: 18% vs. Group 2: 22.2% vs. Group 3: 24.3%, p = 0.83). Conclusions: In non-critical hospitalized patients with COVID-19 pneumonia, neither ivermectin nor hydroxychloroquine decreases the number of in-hospital days, respiratory deterioration, or deaths.

Progress in mechanistically novel treatments for schizophrenia.

Currently available pharmacological treatments for schizophrenia derive their activity mainly by directly modulating the D2 receptor. This mode of action can alleviate the positive symptoms of schizophrenia but do not address the negative or cognitive symptoms of the disease and carry a heavy side effect burden that leads to high levels of patient non-compliance. Novel mechanisms to treat the positive symptoms of schizophrenia with improved tolerability, as well as medicines to treat negative and cognitive symptoms are urgently required. Recent efforts to identify small molecules for schizophrenia with non-D2 mechanisms will be highlighted, with a focus on those that have reached clinical development. Finally, the potential for disease modifying treatments for schizophrenia will also be discussed.

Sequential and Binomial Sampling Plans to Estimate Thrips tabaci Population Density on Onion.

Thrips tabaci Lindeman is a worldwide onion pest that causes economic losses of 10-60%, depending on many factors. Population sampling is essential for applying control tactics and preventing damage by the insect. Conventional sampling methods are criticized as time consuming, while fixed-precision binomial and sequential sampling plans may allow reliable estimations with a more efficient use of time. The aim of this work was to develop binomial and sequential sampling for fast reliable estimation of T. tabaci density on an onion. Forty-one commercial 1.0-ha onion plots were sampled (sample size n = 200) to characterize the spatial distribution of T. tabaci using Taylor's power law (a = 2.586 and b = 1.511). Binomial and sequential enumerative sampling plans were then developed with precision levels of 0.10, 0.15 and 0.25. Sampling plans were validated with bootstrap simulations (1000 samples) using 10 independent data sets. Bootstrap simulation indicated that precision was satisfactory for all repetitions of the sequential sampling plan, while binomial sampling met the fixed precision in 80% of cases. Both methods reduced sampling time by around 80% relative to conventional sampling. These precise and less time-consuming sampling methods can contribute to implementation of control tactics within the integrated pest management approach.

A Neuromotor to Acoustical Jaw-Tongue Projection Model With Application in Parkinson's Disease Hypokinetic Dysarthria.

AIM: The present work proposes the study of the neuromotor activity of the masseter-jaw-tongue articulation during diadochokinetic exercising to establish functional statistical relationships between surface Electromyography (sEMG), 3D Accelerometry (3DAcc), and acoustic features extracted from the speech signal, with the aim of characterizing Hypokinetic Dysarthria (HD). A database of multi-trait signals of recordings from an age-matched control and PD participants are used in the experimental study. HYPOTHESIS: The main assumption is that information between sEMG and 3D acceleration, and acoustic features may be quantified using linear regression methods. METHODS: Recordings from a cohort of eight age-matched control participants (4 males, 4 females) and eight PD participants (4 males, 4 females) were collected during the utterance of a diadochokinetic exercise (the fast repetition of diphthong [aI]). The dynamic and acoustic absolute kinematic velocities produced during the exercises were estimated by acoustic filter inversion and numerical integration and differentiation of the speech signal. The amplitude distributions of the absolute kinematic and acoustic velocities (AKV and AFV) are estimated to allow comparisons in terms of Mutual Information. RESULTS: The regression results show the relationships between sEMG and dynamic and acoustic estimates. The projection methodology may help in understanding the basic neuromotor muscle activity regarding neurodegenerative speech in remote monitoring neuromotor and neurocognitive diseases using speech as the vehicular tool, and in the study of other speech-related disorders. The study also showed strong and significant cross-correlations between articulation kinematics, both for the control and the PD cohorts. The absolute kinematic variables presents an observable difference for the PD participants compared to the control group. CONCLUSION: Kinematic distributions derived from acoustic analysis may be useful biomarkers toward characterizing HD in neuromotor disorders providing new insights into PD.

Defining priority areas for blue whale conservation and investigating overlap with vessel traffic in Chilean Patagonia, using a fast-fitting movement model.

Defining priority areas and risk evaluation is of utmost relevance for endangered species` conservation. For the blue whale (Balaenoptera musculus), we aim to assess environmental habitat selection drivers, priority areas for conservation and overlap with vessel traffic off northern Chilean Patagonia (NCP). For this, we implemented a single-step continuous-time correlated-random-walk model which accommodates observational error and movement parameters variation in relation to oceanographic variables. Spatially explicit predictions of whales' behavioral responses were combined with density predictions from previous species distribution models (SDM) and vessel tracking data to estimate the relative probability of vessels encountering whales and identifying areas where interaction is likely to occur. These estimations were conducted independently for the aquaculture, transport, artisanal fishery, and industrial fishery fleets operating in NCP. Blue whale movement patterns strongly agreed with SDM results, reinforcing our knowledge regarding oceanographic habitat selection drivers. By combining movement and density modeling approaches we provide a stronger support for purported priority areas for blue whale conservation and how they overlap with the main vessel traffic corridor in the NCP. The aquaculture fleet was one order of magnitude larger than any other fleet, indicating it could play a decisive role in modulating potential negative vessel-whale interactions within NCP.

[It's all over! : Complications in the EP lab and their solutions]. / Jetzt ist alles aus! : Komplikationen im EPU-Labor und ihre Lösungen.

In cardiac electrophysiology, invasive procedures like catheter ablations or device implantations are getting increasingly complex. This poses challenges especially for electrophysiologists in training, not only to learn how to perform the procedure, but also how to manage possible complications. The present article uses exemplary case studies to present how to control complications and how to avoid them. The presented cases deal with complications such as air embolism in left atrial procedures, iatrogenic vascular injuries such as aortic dissection or dissection of the coronary sinus, complications and challenges with lead revisions, and pericardial tamponade. In each case, measures for avoidance as well as practical guidance for management are shown when the respective complication occurs.

Systematic Chemogenetic Library Assembly.

Chemogenetic libraries, collections of well-defined chemical probes, provide tremendous value to biomedical research but require substantial effort to ensure diversity as well as quality of the contents. We have assembled a chemogenetic library by data mining and crowdsourcing institutional expertise. We are sharing our approach, lessons learned, and disclosing our current collection of 4,185 compounds with their primary annotated gene targets (https://github.com/Novartis/MoaBox). This physical collection is regularly updated and used broadly both within Novartis and in collaboration with external partners.

Dopamine neurons do not constitute an obligatory stage in the final common path for the evaluation and pursuit of brain stimulation reward.

The neurobiological study of reward was launched by the discovery of intracranial self-stimulation (ICSS). Subsequent investigation of this phenomenon provided the initial link between reward-seeking behavior and dopaminergic neurotransmission. We re-evaluated this relationship by psychophysical, pharmacological, optogenetic, and computational means. In rats working for direct, optical activation of midbrain dopamine neurons, we varied the strength and opportunity cost of the stimulation and measured time allocation, the proportion of trial time devoted to reward pursuit. We found that the dependence of time allocation on the strength and cost of stimulation was similar formally to that observed when electrical stimulation of the medial forebrain bundle served as the reward. When the stimulation is strong and cheap, the rats devote almost all their time to reward pursuit; time allocation falls off as stimulation strength is decreased and/or its opportunity cost is increased. A 3D plot of time allocation versus stimulation strength and cost produces a surface resembling the corner of a plateau (the "reward mountain"). We show that dopamine-transporter blockade shifts the mountain along both the strength and cost axes in rats working for optical activation of midbrain dopamine neurons. In contrast, the same drug shifted the mountain uniquely along the opportunity-cost axis when rats worked for electrical MFB stimulation in a prior study. Dopamine neurons are an obligatory stage in the dominant model of ICSS, which positions them at a key nexus in the final common path for reward seeking. This model fails to provide a cogent account for the differential effect of dopamine transporter blockade on the reward mountain. Instead, we propose that midbrain dopamine neurons and neurons with non-dopaminergic, MFB axons constitute parallel limbs of brain-reward circuitry that ultimately converge on the final-common path for the evaluation and pursuit of rewards.

Liver transplantation in Jehovah's Witnesses: a case series / Experiencia en trasplante hepático para testigos de Jehová: serie de casos

Abstract Introduction: Orthotopic liver transplantation (OLT) is a procedure characterized by high bleeding rates and a significant likelihood of exposure to blood products. Objectives: This case series shows the experience at a referral center for Jehovah's Witnesses (JW) with end-stage liver disease, undergoing OLT. Materials and methods: A search was conducted in our database of JW undergoing OLT between July 2007 and August 2012. The information about their pre-operative condition and progress up to 30 days post-transplantation. Results: Four subjects were identified (3F/1M) with an average age of 42 years (range 22-55). All of them received a multidisciplinary management which included pre-operative optimization of red cell mass, antifibrinolytic prophylaxis, and cell salvage (mean volume of 344mL [range 113-520]). The average intraoperative bleeding volume was of 625mL (range 300-1000). One of the patients presented with a primary graft dysfunction and died, while the rest had a normal postoperative course. Conclusion: It is possible to offer OLT to patients who refuse to receive allogeneic blood transfusions, through a comprehensive approach that includes perioperative hematologic optimization and the use of blood conservation measures, without a significant impact on the outcomes.

Resumen Introducción: El trasplante hepático ortotópico (THO) es un procedimiento caracterizado por índices significativos de sangrado y alta probabilidad de exposición a hemocomponentes. Objetivos: Esta serie de casos muestra la experiencia de un centro de referencia en la atención de testigos de Jehová (TJ) con enfermedad hepática terminal llevados a THO. Materiales y métodos: Se realizó una búsqueda en nuestra base de datos de TJ que hubiesen sido llevados a THO entre julio de 2007 y agosto de 2012. Se registraron datos correspondientes a su estado preoperatorio, manejo perioperatorio y evolución hasta los 30 días postrasplante. Resultados: Se encontraron cuatro sujetos (3M/1H) con una edad promedio de 42 años (rango de 22-55). Todos recibieron un manejo multidisciplinario que incluyó la optimización preoperatoria de su masa eritrocitaria, profilaxis antifibrinolítica y salvamento celular [volumen promedio de 344 ml (rango de 113-520)]. El volumen promedio de sangrado intraoperatorio fue de 625 ml (rango de 300-1000). Uno de los pacientes presentó disfunción primaria del injerto y muerte, mientras que los demás tuvieron un curso posoperatorio convencional. Conclusiones: Es posible ofrecer la posibilidad de THO para sujetos que se niegan a recibir transfusiones alogénicas, por medio de un abordaje integral que incluya la optimización hematológica perioperatoria y la utilización de medidas de conservación sanguínea, sin que esto afecte significativamente los resultados.

Theoretical potential for endometrial cancer prevention through primary risk factor modification: Estimates from the EPIC cohort.

Endometrial cancer (EC) incidence rates vary ~10-fold worldwide, in part due to variation in EC risk factor profiles. Using an EC risk model previously developed in the European EPIC cohort, we evaluated the prevention potential of modified EC risk factor patterns and whether differences in EC incidence between a European population and low-risk countries can be explained by differences in these patterns. Predicted EC incidence rates were estimated over 10 years of follow-up for the cohort before and after modifying risk factor profiles. Risk factors considered were: body mass index (BMI, kg/m2 ), use of postmenopausal hormone therapy (HT) and oral contraceptives (OC) (potentially modifiable); and, parity, ages at first birth, menarche and menopause (environmentally conditioned, but not readily modifiable). Modeled alterations in BMI (to all ≤23 kg/m2 ) and HT use (to all non-HT users) profiles resulted in a 30% reduction in predicted EC incidence rates; individually, longer duration of OC use (to all ≥10 years) resulted in a 42.5% reduction. Modeled changes in not readily modifiable exposures (i.e., those not contributing to prevention potential) resulted in ≤24.6% reduction in predicted EC incidence. Women in the lowest decile of a risk score based on the evaluated exposures had risk similar to a low risk countries; however, this was driven by relatively long use of OCs (median = 23 years). Our findings support avoidance of overweight BMI and of HT use as prevention strategies for EC in a European population; OC use must be considered in the context of benefits and risks.